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Animal Models of Relevance to the Schizophrenia Prodrome

Open AccessPublished:December 08, 2021DOI:https://doi.org/10.1016/j.bpsgos.2021.12.001

      Abstract

      Patients with schizophrenia often undergo a prodromal phase prior to diagnosis. Given the absence of significant therapeutic improvements, attention has recently shifted to the possibility of intervention during this early stage to delay or diminish symptom severity or even prevent onset. Unfortunately, the 20 or so trials of intervention to date have not been successful in either preventing onset or improving long-term outcomes in subjects who are at risk of developing schizophrenia. One reason may be that the biological pathways an effective intervention must target are not static. The prodromal phase typically occurs during late adolescence, a period during which a number of brain circuits and structures are still maturing. We propose that developing a deeper understanding of which circuits/processes and brain structures are still maturing at this time and which processes drive the transition to schizophrenia will take us a step closer to developing better prophylactic interventions. Fortunately, such knowledge is now emerging from clinical studies, complemented by work in animal models. Our task here is to describe what would constitute an appropriate animal model to study and to potentially intervene in such processes. Such a model would allow invasive analysis of the cellular and molecular substrates of the progressive neurobiology that defines the schizophrenia prodrome and hopefully offer valuable insights into potential prophylactic targets.

      Keywords

      SEE COMMENTARY ON PAGE 3
      The existence of a prediagnosis prodromal phase of schizophrenia has been clarified in the past few decades (
      • Yung A.R.
      • McGorry P.D.
      The initial prodrome in psychosis: Descriptive and qualitative aspects.
      ). While the term “prodromal” is applied retrospectively to those patients who ultimately transition to schizophrenia, clinical tools can identify people who are likely to be in this prodromal phase. These tools include assessing the expression of attenuated schizophrenia symptoms, which, when meeting threshold criteria, is termed an at-risk mental state (ARMS), and/or identifying a family history of schizophrenia coupled with functional decline (
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      • et al.
      Mapping the onset of psychosis: The Comprehensive Assessment of At-Risk Mental States.
      ,
      • McGlashan T.H.
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      ). ARMS subjects are commonly identified during late adolescence/early adulthood (
      • McGlashan T.H.
      Early detection and intervention in schizophrenia: Research.
      ), and approximately 15% to 30% will transition to schizophrenia (
      • Hartmann J.A.
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      • Lin A.
      • Wood S.J.
      • et al.
      Declining transition rates to psychotic disorder in “ultra-high risk” clients: Investigation of a dilution effect.
      ). Unfortunately, many patients with schizophrenia experience long-term disability despite treatment with antipsychotics (
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      ), which also cause severe metabolic and movement-related side effects (
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      ). An intervention that prevents the transition from prodrome to schizophrenia would represent a significant major step in treating this debilitating disorder.

      Why Do We Need Animal Models of Relevance to the Schizophrenia Prodrome?

      Antipsychotics are generally effective at reducing psychosis symptoms in a large fraction of patients with an established diagnosis of schizophrenia (
      • McCutcheon R.A.
      • Abi-Dargham A.
      • Howes O.D.
      Schizophrenia, dopamine and the striatum: From biology to symptoms.
      ). These agents have also been trialed in at-risk subjects; however, they have been ultimately unsuccessful in preventing disease onset (
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      108. PREVENT: A randomized controlled trial for the prevention of first-episode psychosis comparing cognitive–behavior therapy (CBT), clinical management, and aripiprazole combined and clinical management and placebo combined.
      ). One reason for this failure may be that the biological targets for an intervention therapy—intended to divert a malleable, still-maturing system away from dysfunction—are quite distinct from those designed to ameliorate chronic symptoms in schizophrenia (Figure 1). Animal models of schizophrenia that permit the assessment of disease course are now required to understand where normal trajectories in brain maturation diverge from a healthy pathway toward dysfunction. Animal models of the prodrome also allow rapid trials of novel prophylactic therapies. Such trials are especially difficult in ARMS subjects, given the low transition rate (15%–30%).
      Figure thumbnail gr1
      Figure 1Maturation of schizophrenia-relevant neurobiological systems. Solid lines indicate normal patterns of maturation in healthy people. Dotted lines indicate findings in patients with schizophrenia. Solid circles indicate that evidence has been acquired in prodromal patients or patients with chronic schizophrenia. Open circles indicate data that are only acquired in patients with chronic schizophrenia, and therefore, prodromal dysfunction is only hypothesized.

      What Constitutes an Animal Model With Relevance to the Prodrome?

      Kapur and colleagues (
      • Tenn C.C.
      • Fletcher P.J.
      • Kapur S.
      A putative animal model of the “prodromal” state of schizophrenia.
      ) posited that an animal model for the schizophrenia prodrome should 1) “be encompassed within a model that has the capacity to show the full-blown phenotype analogous to schizophrenia, 2) embody progression over time, 3) show gradation of pathophysiology rather than an all/none phenotypic outcome, and 4) lead to abnormalities that are analogous to the full-blown phenotype if there are no interventions.”
      While schizophrenia-relevant symptoms emerge in adults (
      • Lipska B.K.
      • Jaskiw G.E.
      • Weinberger D.R.
      Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia.
      ), more recent evidence suggests that behavioral and neurobiological dysfunction show a progressive onset that begins in late adolescence. Therefore, we suggest an additional criterion to those above; in a model of the prodrome, animals must also be assessed during the adolescent period, at which point attenuated schizophrenia-relevant phenotypes may be evident.

      Can Animal Models Be Used to Recapitulate the Neurodevelopmental Progression From the Prodrome to Schizophrenia?

      As the human brain matures during adolescence, it undergoes volumetric changes (
      • Giedd J.N.
      • Blumenthal J.
      • Jeffries N.O.
      • Castellanos F.X.
      • Liu H.
      • Zijdenbos A.
      • et al.
      Brain development during childhood and adolescence: A longitudinal MRI study.
      ,
      • Goddings A.L.
      • Mills K.L.
      • Clasen L.S.
      • Giedd J.N.
      • Viner R.M.
      • Blakemore S.J.
      The influence of puberty on subcortical brain development.
      ,
      • Raznahan A.
      • Shaw P.W.
      • Lerch J.P.
      • Clasen L.S.
      • Greenstein D.
      • Berman R.
      • et al.
      Longitudinal four-dimensional mapping of subcortical anatomy in human development.
      ,
      • Wierenga L.
      • Langen M.
      • Ambrosino S.
      • van Dijk S.
      • Oranje B.
      • Durston S.
      Typical development of basal ganglia, hippocampus, amygdala and cerebellum from age 7 to 24.
      ), continued synaptic maturation (
      • Huttenlocher P.R.
      Synaptic density in human frontal cortex — Developmental changes and effects of aging.
      ,
      • Petanjek Z.
      • Judaš M.
      • Šimic G.
      • Rasin M.R.
      • Uylings H.B.M.
      • Rakic P.
      • Kostovic I.
      Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
      ,
      • Benes F.M.
      • Turtle M.
      • Khan Y.
      • Farol P.
      Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood.
      ), and changes in functional connectivity between brain regions (
      • Tomasi D.
      • Volkow N.D.
      Functional connectivity of substantia nigra and ventral tegmental area: Maturation during adolescence and effects of ADHD.
      ). There are also changes in key neurotransmitters, including dopamine (
      • Jucaite A.
      • Forssberg H.
      • Karlsson P.
      • Halldin C.
      • Farde L.
      Age-related reduction in dopamine D1 receptors in the human brain: From late childhood to adulthood, a positron emission tomography study.
      ,
      • Weickert C.S.
      • Webster M.J.
      • Gondipalli P.
      • Rothmond D.
      • Fatula R.J.
      • Herman M.M.
      • et al.
      Postnatal alterations in dopaminergic markers in the human prefrontal cortex.
      ,
      • Larsen B.
      • Olafsson V.
      • Calabro F.
      • Laymon C.
      • Tervo-Clemmens B.
      • Campbell E.
      • et al.
      Maturation of the human striatal dopamine system revealed by PET and quantitative MRI.
      ), glutamate (
      • Shimizu M.
      • Suzuki Y.
      • Yamada K.
      • Ueki S.
      • Watanabe M.
      • Igarashi H.
      • Nakada T.
      Maturational decrease of glutamate in the human cerebral cortex from childhood to young adulthood: A 1H-MR spectroscopy study.
      ), and GABA (gamma-aminobutyric acid) (
      • Fung S.J.
      • Webster M.J.
      • Sivagnanasundaram S.
      • Duncan C.
      • Elashoff M.
      • Weickert C.S.
      Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
      ,
      • Caballero A.
      • Granberg R.
      • Tseng K.Y.
      Mechanisms contributing to prefrontal cortex maturation during adolescence.
      ), as well as their receptors. Steroids such as testosterone and estrogen also modulate adolescent brain development, leading to sexually dimorphic patterns of maturation (
      • Schulz K.M.
      • Sisk C.L.
      The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development.
      ). Rodents undergo a similar trajectory of behavioral, neurochemical, and hormonal maturation (
      • Workman A.D.
      • Charvet C.J.
      • Clancy B.
      • Darlington R.B.
      • Finlay B.L.
      Modeling transformations of neurodevelopmental sequences across mammalian species.
      ). Although the timing varies between species, sex, and strain, adolescence in rodents spans approximately postnatal day (P) 28 to P56 (
      • Spear L.P.
      The adolescent brain and age-related behavioral manifestations.
      ). This conserved developmental trajectory allows the use of rodents to map the adolescent onset of phenotypes from early neurodevelopmental exposures. Although it is impossible to model the complexity of schizophrenia in an animal, it is possible to assess analogous behavioral phenotypes (
      • Jones C.A.
      • Watson D.J.G.
      • Fone K.C.F.
      Animal models of schizophrenia.
      ).
      Current models of the prodrome can be classified into two main groups. The first group of models are those designed specifically to replicate aspects of the neurobiology of the prodrome (specifically aspects of dopaminergic dysfunction). The second group of models are those based on environmental risk factors or gene variants, where adult phenotypes are already well established. These models have been reexamined within rodent adolescence (P28–P56) to assess the progressive onset of behavioral or neurobiological phenotypes (Table S1). We have extracted the key trends evident in these models and highlighted their relevance to findings in clinical populations.

      Neurobiological Abnormalities in the Prodrome

      Dopamine

      Positron emission tomography neuroimaging studies indicate that patients with chronic schizophrenia have a robust increase in dopamine synthesis capacity in the dorsal striatum (
      • McCutcheon R.
      • Beck K.
      • Jauhar S.
      • Howes O.D.
      Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
      ). Striatal hyperdopaminergia is also evident in at-risk patients who progress to schizophrenia (
      • Howes O.D.
      • Montgomery A.J.
      • Asselin M.C.
      • Murray R.M.
      • Valli I.
      • Tabraham P.
      • et al.
      Elevated striatal dopamine function linked to prodromal signs of schizophrenia.
      ,
      • Egerton A.
      • Chaddock C.A.
      • Winton-Brown T.T.
      • Bloomfield M.A.P.
      • Bhattacharyya S.
      • Allen P.
      • et al.
      Presynaptic striatal dopamine dysfunction in people at ultra-high risk for psychosis: Findings in a second cohort.
      ,
      • Allen P.
      • Luigjes J.
      • Howes O.D.
      • Egerton A.
      • Hirao K.
      • Valli I.
      • et al.
      Transition to psychosis associated with prefrontal and subcortical dysfunction in ultra high-risk individuals.
      ,
      • Howes O.D.
      • Bose S.K.
      • Turkheimer F.
      • Valli I.
      • Egerton A.
      • Valmaggia L.R.
      • et al.
      Dopamine synthesis capacity before onset of psychosis: A prospective [18F]-DOPA PET imaging study.
      ). Longitudinal positron emission tomography imaging indicates that the magnitude of this dopaminergic abnormality increases as symptoms worsen (
      • Howes O.
      • Bose S.
      • Turkheimer F.
      • Valli I.
      • Egerton A.
      • Stahl D.
      • et al.
      Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: A PET study.
      ), suggesting that this may be a target for pharmacological intervention. The dopaminergic system also undergoes substantial refinement during the adolescent period; levels of dopamine in the brain increase from infancy to adulthood (
      • Larsen B.
      • Olafsson V.
      • Calabro F.
      • Laymon C.
      • Tervo-Clemmens B.
      • Campbell E.
      • et al.
      Maturation of the human striatal dopamine system revealed by PET and quantitative MRI.
      ), and levels of dopamine receptors appear to peak at midadolescence, before decreasing to adult levels (
      • Jucaite A.
      • Forssberg H.
      • Karlsson P.
      • Halldin C.
      • Farde L.
      Age-related reduction in dopamine D1 receptors in the human brain: From late childhood to adulthood, a positron emission tomography study.
      ,
      • Weickert C.S.
      • Webster M.J.
      • Gondipalli P.
      • Rothmond D.
      • Fatula R.J.
      • Herman M.M.
      • et al.
      Postnatal alterations in dopaminergic markers in the human prefrontal cortex.
      ).

      Models Designed to Recapitulate the Dopaminergic Abnormalities of the Prodrome

      Amphetamine-sensitization models—in which adult animals are delivered escalating doses of amphetamine, then challenged with amphetamine after withdrawal (
      • Tenn C.C.
      • Fletcher P.J.
      • Kapur S.
      A putative animal model of the “prodromal” state of schizophrenia.
      )—result in schizophrenia-relevant hyperdopaminergia (
      • Featherstone R.E.
      • Kapur S.
      • Fletcher P.J.
      The amphetamine-induced sensitized state as a model of schizophrenia.
      ). Tenn et al. (
      • Tenn C.C.
      • Fletcher P.J.
      • Kapur S.
      A putative animal model of the “prodromal” state of schizophrenia.
      ) adapted this model by replacing amphetamine with saline for some injections (inducing only partial sensitization) to reflect a reduced or prodromal level of dopaminergic dysfunction. This model was designed to replicate the attenuated phenotypic profile rather than the neurobiology of the prodrome because amphetamine elevates striatal dopamine to nonphysiological levels. Interestingly, this model predates the findings of increased dopamine synthesis capacity in prodromal patients by some years.
      The dopamine D2 receptor (D2R) overexpression model of schizophrenia increases D2R density transgenically in the striatum (
      • Kellendonk C.
      • Simpson E.H.
      • Polan H.J.
      • Malleret G.
      • Vronskaya S.
      • Winiger V.
      • et al.
      Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.
      ). Although increased D2R density is not a major finding in schizophrenia (
      • Howes O.D.
      • Kambeitz J.
      • Kim E.
      • Stahl D.
      • Slifstein M.
      • Abi-Dargham A.
      • Kapur S.
      The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
      ), this model replicates increased striatal dopaminergic transmission, which is a key component of the schizophrenia prodrome. Adult D2R overexpression mice display a number of cognitive- and negative-symptom phenotypes (
      • Simpson E.H.
      • Kellendonk C.
      Insights about striatal circuit function and schizophrenia from a mouse model of dopamine D2 receptor upregulation.
      ), and juvenile D2R overexpression animals show deficits in social interaction (
      • Kabitzke P.A.
      • Simpson E.H.
      • Kandel E.R.
      • Balsam P.D.
      Social behavior in a genetic model of dopamine dysfunction at different neurodevelopmental time points.
      ). These findings lend support to the theory that cortical dysfunction (which contributes to the cognitive and negative symptoms of schizophrenia) may be secondary to striatal hyperdopaminergia (
      • Simpson E.H.
      • Kellendonk C.
      • Kandel E.
      A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia.
      ).
      Enhanced Dopamine in Prodromal Schizophrenia (EDiPS) is a model described by Petty et al. (
      • Petty A.
      • Cui X.
      • Tesiram Y.
      • Kirik D.
      • Howes O.
      • Eyles D.
      Enhanced Dopamine in Prodromal Schizophrenia (EDiPS): A new animal model of relevance to schizophrenia.
      ) that uses a transgenic construct to increase dopamine-synthesizing enzymes in the dorsal striatum of rats from adolescence (P35). Adult animals show increased amphetamine-induced dopamine release in this region, reflecting the presynaptic dorsal striatal dopaminergic abnormality evident in the prodrome. Adult EDiPS animals also display increased amphetamine-induced hyperlocomotion and prepulse inhibition (PPI) deficits (
      • Petty A.
      • Cui X.
      • Tesiram Y.
      • Kirik D.
      • Howes O.
      • Eyles D.
      Enhanced Dopamine in Prodromal Schizophrenia (EDiPS): A new animal model of relevance to schizophrenia.
      ). When assessed longitudinally from juvenile to adult ages, these behaviors show a progressive onset, similar to the progression of symptoms seen in prodromal patients (
      • Petty A.
      • Cui X.
      • Ali A.
      • Du Z.
      • Srivastav S.
      • Kesby J.P.
      • et al.
      Positive symptom phenotypes appear progressively in “EDiPS”, a new animal model of the schizophrenia prodrome.
      ). This model can now be used to clarify the downstream effects of increased dopamine synthesis and release during adolescence.

      Dopaminergic Dysfunction in Animal Models of Schizophrenia

      Studies using maternal immune activation (MIA) (
      • Vuillermot S.
      • Weber L.
      • Feldon J.
      • Meyer U.
      A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia.
      ,
      • Zuckerman L.
      • Rehavi M.
      • Nachman R.
      • Weiner I.
      Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: A novel neurodevelopmental model of schizophrenia.
      ,
      • Hadar R.
      • Soto-Montenegro M.L.
      • Götz T.
      • Wieske F.
      • Sohr R.
      • Desco M.
      • et al.
      Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course.
      ,
      • Romero E.
      • Guaza C.
      • Castellano B.
      • Borrell J.
      Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: Implications for the etiopathology of schizophrenia.
      ,
      • Baharnoori M.
      • Bhardwaj S.K.
      • Srivastava L.K.
      Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring.
      ), neonatal brain lesion of the entorhinal cortex or medial prefrontal cortex (mPFC) (
      • Uehara T.
      • Tanii Y.
      • Sumiyoshi T.
      • Kurachi M.
      Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.
      ,
      • Flores G.
      • Wood G.K.
      • Liang J.J.
      • Quirion R.
      • Srivastava L.K.
      Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex.
      ,
      • Boyce P.J.
      • Finlay J.M.
      Neonatal depletion of cortical dopamine: Effects on dopamine turnover and motor behavior in juvenile and adult rats.
      ,
      • Boyce P.J.
      • Finlay J.M.
      Extracellular dopamine and norepinephrine in the developing rat prefrontal cortex: Transient effects of early partial loss of dopamine.
      ), pre- and postnatal stress (
      • Silvagni A.
      • Barros V.G.
      • Mura C.
      • Antonelli M.C.
      • Carboni E.
      Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: An ‘in vivo’ microdialysis study in adolescent and young adult rats.
      ,
      • Gomes F.V.
      • Zhu X.
      • Grace A.A.
      The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability [published correction appears in Mol Psychiatry 2020; 25:3449].
      ), genetic manipulation (
      • Niwa M.
      • Kamiya A.
      • Murai R.
      • Kubo K.
      • Gruber A.J.
      • Tomita K.
      • et al.
      Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
      ), and the gestational MAM (methylazoxymethanol acetate) model (
      • Sonnenschein S.F.
      • Grace A.A.
      Peripubertal mGluR2/3 agonist treatment prevents hippocampal dysfunction and dopamine system hyperactivity in adulthood in MAM model of schizophrenia.
      ) have assessed dopaminergic dysfunction in both adult and juvenile animals. In the dorsal striatum, MIA-exposed and neonatally lesioned animals showed increased extracellular levels of dopamine at baseline and following potassium-induced dopamine release, as well as an increased number of dopamine D1- and D2-like receptors as adults, but not as juveniles (compared with age-matched control animals) (
      • Vuillermot S.
      • Weber L.
      • Feldon J.
      • Meyer U.
      A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia.
      ,
      • Zuckerman L.
      • Rehavi M.
      • Nachman R.
      • Weiner I.
      Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: A novel neurodevelopmental model of schizophrenia.
      ,
      • Uehara T.
      • Tanii Y.
      • Sumiyoshi T.
      • Kurachi M.
      Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.
      ,
      • Flores G.
      • Wood G.K.
      • Liang J.J.
      • Quirion R.
      • Srivastava L.K.
      Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex.
      ). In juvenile MIA-exposed, neonatally lesioned, and prenatally stressed animals, findings in the nucleus accumbens (NAc) were variable, with levels of extracellular and tissue homogenate dopamine increased (
      • Hadar R.
      • Soto-Montenegro M.L.
      • Götz T.
      • Wieske F.
      • Sohr R.
      • Desco M.
      • et al.
      Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course.
      ,
      • Silvagni A.
      • Barros V.G.
      • Mura C.
      • Antonelli M.C.
      • Carboni E.
      Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: An ‘in vivo’ microdialysis study in adolescent and young adult rats.
      ), decreased (
      • Romero E.
      • Guaza C.
      • Castellano B.
      • Borrell J.
      Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: Implications for the etiopathology of schizophrenia.
      ,
      • Boyce P.J.
      • Finlay J.M.
      Neonatal depletion of cortical dopamine: Effects on dopamine turnover and motor behavior in juvenile and adult rats.
      ), or unchanged (
      • Uehara T.
      • Tanii Y.
      • Sumiyoshi T.
      • Kurachi M.
      Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.
      ). However, when assessed as adults, baseline (tissue homogenate) and amphetamine-induced dopamine levels in the NAc were almost universally increased compared with adult control animals (
      • Hadar R.
      • Soto-Montenegro M.L.
      • Götz T.
      • Wieske F.
      • Sohr R.
      • Desco M.
      • et al.
      Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course.
      ,
      • Romero E.
      • Guaza C.
      • Castellano B.
      • Borrell J.
      Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: Implications for the etiopathology of schizophrenia.
      ,
      • Uehara T.
      • Tanii Y.
      • Sumiyoshi T.
      • Kurachi M.
      Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.
      ,
      • Silvagni A.
      • Barros V.G.
      • Mura C.
      • Antonelli M.C.
      • Carboni E.
      Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: An ‘in vivo’ microdialysis study in adolescent and young adult rats.
      ). Levels of the dopamine transporter were downregulated in the NAc in juvenile MIA-exposed and neonatally lesioned animals but returned to control levels by adulthood (
      • Vuillermot S.
      • Weber L.
      • Feldon J.
      • Meyer U.
      A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia.
      ,
      • Baharnoori M.
      • Bhardwaj S.K.
      • Srivastava L.K.
      Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring.
      ,
      • Flores G.
      • Wood G.K.
      • Liang J.J.
      • Quirion R.
      • Srivastava L.K.
      Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex.
      ). As in the dorsal striatum, D1 and D2 receptors in the NAc were typically unaltered compared with control animals in MIA-exposed and neonatally lesioned animals as juveniles but were increased in adulthood compared with control adults (
      • Vuillermot S.
      • Weber L.
      • Feldon J.
      • Meyer U.
      A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia.
      ,
      • Flores G.
      • Wood G.K.
      • Liang J.J.
      • Quirion R.
      • Srivastava L.K.
      Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex.
      ). In the PFC, dopamine levels in neonatally lesioned and genetically manipulated animals were unaltered in juveniles (compared with age-matched control animals). However, in contrast to striatal findings, PFC dopamine was decreased in adult animals from these models (
      • Uehara T.
      • Tanii Y.
      • Sumiyoshi T.
      • Kurachi M.
      Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.
      ,
      • Niwa M.
      • Kamiya A.
      • Murai R.
      • Kubo K.
      • Gruber A.J.
      • Tomita K.
      • et al.
      Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
      ). One exception was the PFC lesion model, for which dopamine levels were decreased at P30, P45, and P60, relative to age-matched unlesioned control animals (
      • Boyce P.J.
      • Finlay J.M.
      Neonatal depletion of cortical dopamine: Effects on dopamine turnover and motor behavior in juvenile and adult rats.
      ,
      • Boyce P.J.
      • Finlay J.M.
      Extracellular dopamine and norepinephrine in the developing rat prefrontal cortex: Transient effects of early partial loss of dopamine.
      ). Finally, in the MAM model, dopamine neuron activity in the ventral tegmental area was normal in juvenile animals (compared with age-matched control animals), but increased in adulthood (
      • Sonnenschein S.F.
      • Grace A.A.
      Peripubertal mGluR2/3 agonist treatment prevents hippocampal dysfunction and dopamine system hyperactivity in adulthood in MAM model of schizophrenia.
      ). In contrast, stress during adolescence (from P31 to P40) induced an increase in ventral tegmental area dopamine neuron activity when assessed 1 to 2 weeks later, whereas stress during adulthood resulted in decreased dopamine neuron activity in the ventral tegmental area (
      • Gomes F.V.
      • Zhu X.
      • Grace A.A.
      The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability [published correction appears in Mol Psychiatry 2020; 25:3449].
      ). Overall, most dopaminergic factors were normal in juveniles but were abnormal (generally increased) by adulthood compared with age-matched control animals.

      Glutamate/Glutamine

      Proton magnetic resonance spectroscopy (1H-MRS) studies have revealed elevated levels of glutamate and/or its precursor glutamine in the striatum and medial temporal lobe of patients with schizophrenia (
      • Merritt K.
      • Egerton A.
      • Kempton M.J.
      • Taylor M.J.
      • McGuire P.K.
      Nature of glutamate alterations in schizophrenia: A meta-analysis of proton magnetic resonance spectroscopy studies.
      ), although these findings may be affected by treatment and/or disease course (
      • Merritt K.
      • McGuire P.K.
      • Egerton A.
      • Aleman A.
      • Block W.
      • et al.
      1H-MRS in Schizophrenia Investigators
      Association of age, antipsychotic medication, and symptom severity in schizophrenia with proton magnetic resonance spectroscopy brain glutamate level: A mega-analysis of individual participant-level data.
      ). ARMS subjects who later transition to schizophrenia show elevated levels of glutamate in the dorsal striatum (
      • de la Fuente-Sandoval C.
      • León-Ortiz P.
      • Favila R.
      • Stephano S.
      • Mamo D.
      • Ramírez-Bermúdez J.
      • Graff-Guerrero A.
      Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis.
      ,
      • de la Fuente-Sandoval C.
      • León-Ortiz P.
      • Azcárraga M.
      • Favila R.
      • Stephano S.
      • Graff-Guerrero A.
      Striatal glutamate and the conversion to psychosis: A prospective 1H-MRS imaging study.
      ) and hippocampus (
      • Bossong M.G.
      • Antoniades M.
      • Azis M.
      • Samson C.
      • Quinn B.
      • Bonoldi I.
      • et al.
      Association of hippocampal glutamate levels with adverse outcomes in individuals at clinical high risk for psychosis.
      ) [but not the medial temporal lobe (
      • Wood S.J.
      • Kennedy D.
      • Phillips L.J.
      • Seal M.L.
      • Yücel M.
      • Nelson B.
      • et al.
      Hippocampal pathology in individuals at ultra-high risk for psychosis: A multi-modal magnetic resonance study.
      )] in comparison with ARMS subjects who do not transition and with healthy control subjects. As far as we are aware, no study has performed 1H-MRS longitudinally in ARMS patients. 1H-MRS studies in healthy people indicate that levels of glutamate are stable through adolescence in the basal ganglia (
      • Blüml S.
      • Wisnowski J.L.
      • Nelson Jr., M.D.
      • Paquette L.
      • Gilles F.H.
      • Kinney H.C.
      • Panigrahy A.
      Metabolic maturation of the human brain from birth through adolescence: Insights from in vivo magnetic resonance spectroscopy.
      ) but decline in cortical areas during this time (
      • Shimizu M.
      • Suzuki Y.
      • Yamada K.
      • Ueki S.
      • Watanabe M.
      • Igarashi H.
      • Nakada T.
      Maturational decrease of glutamate in the human cerebral cortex from childhood to young adulthood: A 1H-MR spectroscopy study.
      ).
      Glutamatergic abnormalities have also been examined in preclinical models of the prodrome. A study using longitudinal 1H-MRS found no difference in levels of glutamate or glutamax (glutamate+glutamine) between MIA-exposed offspring and control animals in the PFC at any age (
      • Vernon A.C.
      • So P.W.
      • Lythgoe D.J.
      • Chege W.
      • Cooper J.D.
      • Williams S.C.R.
      • Kapur S.
      Longitudinal in vivo maturational changes of metabolites in the prefrontal cortex of rats exposed to polyinosinic-polycytidylic acid in utero.
      ). Upregulation of NMDA receptor subunits was seen in the PFC of adult but not juvenile MIA-exposed animals compared with age-matched control animals (
      • Hao K.
      • Su X.
      • Luo B.
      • Cai Y.
      • Chen T.
      • Yang Y.
      • et al.
      Prenatal immune activation induces age-related alterations in rat offspring: Effects upon NMDA receptors and behaviors.
      ). In addition, increased NMDA-mediated excitation of pyramidal cells was seen in the PFC of adult, but not juvenile, neonatally lesioned animals, compared with unlesioned, age-matched control animals (
      • Tseng K.Y.
      • Lewis B.L.
      • Lipska B.K.
      • O’Donnell P.
      Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia.
      ). These findings may reflect an attempt at compensatory upregulation of NMDA signaling, which would be consistent with the hypofunction of NMDA receptors seen in patients with schizophrenia (
      • Balu D.T.
      The NMDA receptor and schizophrenia: From pathophysiology to treatment.
      ). Given the region-specific abnormalities seen in clinical studies, we also await analysis of striatal (rather than cortical) glutamate in these models.

      Structural Abnormalities

      Longitudinal studies indicate that as prodromal subjects transition to schizophrenia, normal structural changes (decreasing cortical gray matter volume, increasing lateral ventricle volume) are evident earlier and progress more rapidly compared with healthy control subjects and compared with those at-risk subjects who did not transition (
      • Cannon T.D.
      • Chung Y.
      • He G.
      • Sun D.
      • Jacobson A.
      • van Erp T.G.M.
      • et al.
      Progressive reduction in cortical thickness as psychosis develops: A multisite longitudinal neuroimaging study of youth at elevated clinical risk.
      ,
      • Ziermans T.B.
      • Schothorst P.F.
      • Schnack H.G.
      • Koolschijn P.C.M.P.
      • Kahn R.S.
      • van Engeland H.
      • Durston S.
      Progressive structural brain changes during development of psychosis.
      ). There is also evidence that the normal trajectory of white matter maturation is disrupted in ARMS subjects who later transition, including an accelerated reduction in corpus callosum volume during early adulthood, compared with healthy control subjects (
      • Merritt K.
      • Luque Laguna P.
      • Irfan A.
      • David A.S.
      Longitudinal structural MRI findings in individuals at genetic and clinical high risk for psychosis: A systematic review.
      ). Finally, there is evidence that hypermetabolism in the hippocampus may contribute to structural changes in this region in ARMS subjects (
      • Schobel S.A.
      • Chaudhury N.H.
      • Khan U.A.
      • Paniagua B.
      • Styner M.A.
      • Asllani I.
      • et al.
      Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.
      ), indicating a potential link between brain activity and structural abnormalities.
      Progressive alterations in brain structure are also evident in preclinical models of the prodrome. Two studies in MIA-exposed animals used longitudinal magnetic resonance imaging to assess the progression of brain structural abnormalities. The first study found that juvenile MIA-exposed animals showed reduced cortical gray matter volumes and enlarged ventricles compared with juvenile control animals and that these abnormalities worsened as animals matured (
      • Piontkewitz Y.
      • Arad M.
      • Weiner I.
      Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat.
      ). However, a more recent study found that while early trajectories of structural development were altered between P38 and P60, in MIA-exposed mice, many of these volumetric abnormalities normalized by P90 (
      • Guma E.
      • Bordignon P.D.C.
      • Devenyi G.A.
      • Gallino D.
      • Anastassiadis C.
      • Cvetkovska V.
      • et al.
      Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: An integrated neuroimaging, behavioral, and transcriptional study.
      ). Importantly, this second study also found an association between volumetric abnormalities and behavioral phenotypes in juvenile MIA-exposed animals, which was absent in adulthood. Decreased white matter volumes have also been shown in juvenile MIA-exposed and genetically manipulated animals, and these animals showed accelerated white matter volume reduction (compared with maturing control animals) (
      • Intson K.
      • van Eede M.C.
      • Islam R.
      • Milenkovic M.
      • Yan Y.
      • Salahpour A.
      • et al.
      Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation.
      ,
      • Crum W.R.
      • Sawiak S.J.
      • Chege W.
      • Cooper J.D.
      • Williams S.C.R.
      • Vernon A.C.
      Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study.
      ). Therefore, these models can reflect certain progressive volumetric changes evident in prodromal patients.

      Neurochemical Abnormalities in Patients With Chronic Schizophrenia That May Be Relevant to the Prodrome

      Some cellular and molecular factors can only be assessed in postmortem tissue, which to date has come mainly from patients with chronic schizophrenia. However, evidence acquired from healthy people (and healthy rodents) indicates that neurotransmitter systems undergo profound remodeling during adolescence. Therefore, the dysfunction apparent in patients with chronic schizophrenia may have its origins during the prodrome.

      Parvalbumin Interneurons

      Parvalbumin (PV) interneurons are an important class of GABAergic (gamma-aminobutyric acidergic) interneurons that regulate cortical function. Decreased PV interneuron density is one of the most well-replicated cortical cellular abnormalities in patients with schizophrenia (
      • Fung S.J.
      • Webster M.J.
      • Sivagnanasundaram S.
      • Duncan C.
      • Elashoff M.
      • Weickert C.S.
      Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
      ,
      • Kaar S.J.
      • Angelescu I.
      • Marques T.R.
      • Howes O.D.
      Pre-frontal parvalbumin interneurons in schizophrenia: A meta-analysis of post-mortem studies.
      ). Because the number of PV interneurons increases in early postnatal life (
      • Fung S.J.
      • Webster M.J.
      • Sivagnanasundaram S.
      • Duncan C.
      • Elashoff M.
      • Weickert C.S.
      Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
      ) and PV interneuron firing properties continue to mature into adulthood (
      • Caballero A.
      • Flores-Barrera E.
      • Cass D.K.
      • Tseng K.Y.
      Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence.
      ), this cellular abnormality may originate in the prodrome. Animal models have been used to explore this possibility. The number of PV+ cells and the abundance of PV protein was found to be decreased in the hippocampus and PFC at both juvenile and adult ages (relative to age-matched control animals) in the MAM (
      • Gill K.M.
      • Grace A.A.
      Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model.
      ,
      • Chen L.
      • Perez S.M.
      • Lodge D.J.
      An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia.
      ), prenatal MK-801 (dizocilpine) (
      • Abekawa T.
      • Ito K.
      • Nakagawa S.
      • Koyama T.
      Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats.
      ,
      • Abekawa T.
      • Ito K.
      • Nakato Y.
      • Koyama T.
      Developmental GABAergic deficit enhances methamphetamine-induced apoptosis.
      ), and neonatal MK-801 (
      • Li J.T.
      • Zhao Y.Y.
      • Wang H.L.
      • Wang X.D.
      • Su Y.A.
      • Si T.M.
      Long-term effects of neonatal exposure to MK-801 on recognition memory and excitatory-inhibitory balance in rat hippocampus.
      ) models. In addition, a stress model found that the number of PV+ cells was unchanged immediately following 9 days of adolescent stress exposure (at P41) but was decreased from P51 into adulthood (P75) (
      • Gomes F.V.
      • Zhu X.
      • Grace A.A.
      The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability [published correction appears in Mol Psychiatry 2020; 25:3449].
      ). In contrast, when adult animals were exposed to the same stress paradigm, no decrease in PV+ cells was seen. Given the critical role of these interneurons for normal brain development, early changes in the PV system may contribute to downstream neurobiological and structural abnormalities evident in the prodrome. Interestingly, in two genetic models of schizophrenia—Disc1 knockdown (
      • Niwa M.
      • Kamiya A.
      • Murai R.
      • Kubo K.
      • Gruber A.J.
      • Tomita K.
      • et al.
      Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
      ) and a model of 22q.11.2 deletion (
      • Piskorowski R.A.
      • Nasrallah K.
      • Diamantopoulou A.
      • Mukai J.
      • Hassan S.I.
      • Siegelbaum S.A.
      • et al.
      Age-dependent specific changes in area CA2 of the hippocampus and social memory deficit in a mouse model of the 22q11.2 deletion syndrome.
      )—the number of PV+ cells was decreased in adult but not juvenile animals (relative to age-matched control animals) in the mPFC and hippocampus, respectively. Whether these changes in PV expression reflect changes in PV firing properties is unknown.

      Synaptic Pruning/Dendritic Morphology

      A number of studies (primarily in postmortem tissue) indicate that patients with schizophrenia show decreased presynaptic and/or dendritic spine density in cortical areas (
      • Glausier J.R.
      • Lewis D.A.
      Dendritic spine pathology in schizophrenia.
      ,
      • Osimo E.F.
      • Beck K.
      • Reis Marques T.
      • Howes O.D.
      Synaptic loss in schizophrenia: A meta-analysis and systematic review of synaptic protein and mRNA measures.
      ,
      • Onwordi E.C.
      • Halff E.F.
      • Whitehurst T.
      • Mansur A.
      • Cotel M.C.
      • Wells L.
      • et al.
      Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.
      ). Pruning of synapses and maturation of dendritic morphology continues in the cortex during adolescence and into adulthood (
      • Petanjek Z.
      • Judaš M.
      • Šimic G.
      • Rasin M.R.
      • Uylings H.B.M.
      • Rakic P.
      • Kostovic I.
      Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
      ), and altered spine density or morphology may therefore be evident in the prodrome. In preclinical models, disruption of the normal maturation of synaptic density and dendritic morphology was seen in juvenile and adult MIA-exposed offspring (
      • Baharnoori M.
      • Brake W.G.
      • Srivastava L.K.
      Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats.
      ) and animals exposed to prenatal stress (
      • Markham J.A.
      • Mullins S.E.
      • Koenig J.I.
      Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress.
      ,
      • Martínez-Téllez R.I.
      • Hernández-Torres E.
      • Gamboa C.
      • Flores G.
      Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring.
      ). In a genetic model of schizophrenia in which C4A, a complement gene, was constitutively overexpressed, synaptic density in the mPFC was decreased in adult animals (P60), but not in juveniles (P40) compared with age-matched control animals (
      • Yilmaz M.
      • Yalcin E.
      • Presumey J.
      • Aw E.
      • Ma M.
      • Whelan C.W.
      • et al.
      Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
      ). Therefore, changes in synaptic density and/or spine morphology may be evident even prior to schizophrenia diagnosis.

      Immune Response

      Mounting evidence suggests that elevated neuroinflammation is a feature of chronic schizophrenia (
      • van Kesteren C.F.M.G.
      • Gremmels H.
      • de Witte L.D.
      • Hol E.M.
      • Van Gool A.R.
      • Falkai P.G.
      • et al.
      Immune involvement in the pathogenesis of schizophrenia: A meta-analysis on postmortem brain studies.
      ,
      • Marques T.R.
      • Ashok A.H.
      • Pillinger T.
      • Veronese M.
      • Turkheimer F.E.
      • Dazzan P.
      • et al.
      Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies.
      ). However, there is contradictory evidence from neuroimaging studies regarding whether microglial activity (a marker of neuroinflammation) is increased in ARMS subjects (
      • Bloomfield P.S.
      • Selvaraj S.
      • Veronese M.
      • Rizzo G.
      • Bertoldo A.
      • Owen D.R.
      • et al.
      Microglial activity in people at ultra high risk of psychosis and in schizophrenia: An [(11)C]PBR28 PET brain imaging study [published correction appears in Am J Psychiatry 2017; 174:402].
      ,
      • Di Biase M.A.
      • Zalesky A.
      • O’keefe G.
      • Laskaris L.
      • Baune B.T.
      • Weickert C.S.
      • et al.
      PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia.
      ). This is further complicated by potential limitations of the neuroimaging tracers used in vivo (
      • Marques T.R.
      • Ashok A.H.
      • Pillinger T.
      • Veronese M.
      • Turkheimer F.E.
      • Dazzan P.
      • et al.
      Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies.
      ). In preclinical studies, immune factors have been assessed in both juvenile and adult animals predominantly in MIA-exposed offspring. These studies have found evidence of increased microglia activation throughout the brain (
      • Eßlinger M.
      • Wachholz S.
      • Manitz M.P.
      • Plümper J.
      • Sommer R.
      • Juckel G.
      • Friebe A.
      Schizophrenia associated sensory gating deficits develop after adolescent microglia activation.
      ), specifically in the hippocampus, mPFC (
      • Ding S.
      • Hu Y.
      • Luo B.
      • Cai Y.
      • Hao K.
      • Yang Y.
      • et al.
      Age-related changes in neuroinflammation and prepulse inhibition in offspring of rats treated with Poly I:C in early gestation.
      ), and striatum (
      • Ribeiro B.M.M.
      • do Carmo M.R.S.
      • Freire R.S.
      • Rocha N.F.M.
      • Borella V.C.M.
      • de Menezes A.T.
      • et al.
      Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine.
      ) in both juvenile and adult animals, compared with age-matched control animals. Altered levels of proinflammatory cytokines have also been seen in the brains of both juvenile and adult MIA-exposed animals (
      • Eßlinger M.
      • Wachholz S.
      • Manitz M.P.
      • Plümper J.
      • Sommer R.
      • Juckel G.
      • Friebe A.
      Schizophrenia associated sensory gating deficits develop after adolescent microglia activation.
      ,
      • Ding S.
      • Hu Y.
      • Luo B.
      • Cai Y.
      • Hao K.
      • Yang Y.
      • et al.
      Age-related changes in neuroinflammation and prepulse inhibition in offspring of rats treated with Poly I:C in early gestation.
      ,
      • Manitz M.P.
      • Plümper J.
      • Demir S.
      • Ahrens M.
      • Eßlinger M.
      • Wachholz S.
      • et al.
      Flow cytometric characterization of microglia in the offspring of polyI:C treated mice.
      ,
      • Garay P.A.
      • Hsiao E.Y.
      • Patterson P.H.
      • McAllister A.K.
      Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development.
      ,
      • Clark S.M.
      • Notarangelo F.M.
      • Li X.
      • Chen S.
      • Schwarcz R.
      • Tonelli L.H.
      Maternal immune activation in rats blunts brain cytokine and kynurenine pathway responses to a second immune challenge in early adulthood.
      ). However, because the MIA model specifically induces an inflammatory response, studies in models that do not target the immune system would provide stronger evidence for the centrality of neuroinflammatory abnormalities in the schizophrenia prodrome. Oxidative stress, a correlate of neuroinflammation, has also been seen in a number of animal models in adulthood (
      • Steullet P.
      • Cabungcal J.H.
      • Coyle J.
      • Didriksen M.
      • Gill K.
      • Grace A.A.
      • et al.
      Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.
      ). However, to our knowledge, the effects of oxidative stress on juvenile animals in these models has not yet been assessed.

      Progression of Symptoms in the Prodrome

      Attenuated cognitive and negative symptoms are typically evident in prodromal patients prior to the expression of attenuated psychosis symptoms (
      • Reichenberg A.
      • Caspi A.
      • Harrington H.
      • Houts R.
      • Keefe R.S.E.
      • Murray R.M.
      • et al.
      Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: A 30-year study.
      ). In preclinical studies, negative symptom– and cognition-relevant phenotypes are poorly assessed (25 of 103 studies examined in Table S1) and have been reported in juvenile animals from some but not all models. Because these symptom domains are highly sensitive predictors of functional outcomes for prodromal patients (
      • Johnstone E.C.
      • Ebmeier K.P.
      • Miller P.
      • Owens D.G.C.
      • Lawrie S.M.
      Predicting schizophrenia: Findings from the Edinburgh High-Risk Study.
      ,
      • Gur R.E.
      • March M.
      • Calkins M.E.
      • Weittenhiller L.
      • Wolf D.H.
      • Turetsky B.I.
      • Gur R.C.
      Negative symptoms in youths with psychosis spectrum features: Complementary scales in relation to neurocognitive performance and function.
      ), this is a critical omission.
      Positive symptoms are often absent or minimal prior to a subject fulfilling ARMS criteria. This pattern is also observed in preclinical models; phenotypes relevant to psychosis are typically absent (or attenuated) when assessed at pre- or peripubertal stages, only to emerge by adulthood (Table S1). This convergent pattern suggests two potential mechanisms. First, early adverse exposures may create some hidden lesion or dysconnectivity for which the malleable adolescent brain can compensate. This becomes unmasked or decompensated once the animal matures and these plastic circuits can no longer be recruited. Second, an early adverse exposure may leave circuitry intact but change some undetermined chemical or hormonal signal that the brain does not require until puberty. These concepts are not mutually exclusive and have been discussed in greater detail in a recent review (
      • Eyles D.W.
      How do established developmental risk-factors for schizophrenia change the way the brain develops?.
      ).

      Progression of Endophenotypes in the Prodrome

      Deficits in PPI and mismatch negativity (MMN) are considered endophenotypes for schizophrenia (
      • Owens E.M.
      • Bachman P.
      • Glahn D.C.
      • Bearden C.E.
      Electrophysiological endophenotypes for schizophrenia.
      ) and have also been found in ARMS cohorts (
      • Quednow B.B.
      • Frommann I.
      • Berning J.
      • Kühn K.U.
      • Maier W.
      • Wagner M.
      Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia.
      ,
      • Erickson M.A.
      • Ruffle A.
      • Gold J.M.
      A meta-analysis of mismatch negativity in schizophrenia: From clinical risk to disease specificity and progression.
      ). Furthermore, PPI deficits worsen in ARMS subjects who transition to schizophrenia (
      • Ziermans T.
      • Schothorst P.
      • Magnée M.
      • van Engeland H.
      • Kemner C.
      Reduced prepulse inhibition in adolescents at risk for psychosis: A 2-year follow-up study.
      ), and MMN abnormalities are associated with transition likelihood (
      • Erickson M.A.
      • Ruffle A.
      • Gold J.M.
      A meta-analysis of mismatch negativity in schizophrenia: From clinical risk to disease specificity and progression.
      ). In preclinical models of relevance to the prodrome, PPI deficits generally appear postpubertally (21 of 35 studies), suggesting that the circuitry underlying PPI is resilient to early developmental insults. Although MMN has been assessed in adult animals across a range of models (
      • Harms L.
      Mismatch responses and deviance detection in N-methyl-D-aspartate (NMDA) receptor hypofunction and developmental models of schizophrenia.
      ), to our knowledge it has not yet been assessed in juvenile animals from these models. Because MMN may be a useful predictor of transition to schizophrenia, this is a significant gap in the field.

      Outcomes of Interventions in Current Models of the Prodrome

      In a number of models of the prodrome, transient intervention with antipsychotic drugs during adolescence prevented the appearance of schizophrenia-relevant behavioral (
      • Lipska B.K.
      • Jaskiw G.E.
      • Weinberger D.R.
      Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia.
      ,
      • Piontkewitz Y.
      • Assaf Y.
      • Weiner I.
      Clozapine administration in adolescence prevents postpubertal emergence of brain structural pathology in an animal model of schizophrenia.
      ,
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      • Schwarz M.J.
      • Feldon J.
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      ,
      • Lipska B.K.
      • Chrapusta S.J.
      • Egan M.F.
      • Weinberger D.R.
      Neonatal excitotoxic ventral hippocampal damage alters dopamine response to mild repeated stress and to chronic haloperidol.
      ,
      • Richtand N.M.
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      Risperidone pretreatment prevents elevated locomotor activity following neonatal hippocampal lesions.
      ), structural (
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      Risperidone administered during asymptomatic period of adolescence prevents the emergence of brain structural pathology and behavioral abnormalities in an animal model of schizophrenia.
      ), and neuropathological (
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      ) phenotypes in adult animals, even after drug washout. Nonantipsychotic compounds also showed efficacy in reducing the expression of schizophrenia-relevant phenotypes (
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      Peripubertal mGluR2/3 agonist treatment prevents hippocampal dysfunction and dopamine system hyperactivity in adulthood in MAM model of schizophrenia.
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      ,
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      Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation.
      ,
      • Richtand N.M.
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      Fluoxetine and aripiprazole treatment following prenatal immune activation exert longstanding effects on rat locomotor response.
      ,
      • Du Y.
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      Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia.
      ,
      • Du Y.
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      Amygdala hyperactivity in MAM model of schizophrenia is normalized by peripubertal diazepam administration.
      ,
      • Bator E.
      • Latusz J.
      • Radaszkiewicz A.
      • Wędzony K.
      • Maćkowiak M.
      Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia.
      ,
      • Cabungcal J.H.
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      • Lewis E.
      • Tejeda H.A.
      • Piantadosi P.
      • Pollock C.
      • et al.
      Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.
      ,
      • Swanepoel T.
      • Möller M.
      • Harvey B.H.
      N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.
      ,
      • Li M.L.
      • Gulchina Y.
      • Monaco S.A.
      • Xing B.
      • Ferguson B.R.
      • Li Y.C.
      • et al.
      Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia.
      ,
      • Gomes F.V.
      • Guimarães F.S.
      • Grace A.A.
      Effects of pubertal cannabinoid administration on attentional set-shifting and dopaminergic hyper-responsivity in a developmental disruption model of schizophrenia.
      ,
      • Osborne A.L.
      • Solowij N.
      • Babic I.
      • Huang X.F.
      • Weston-Green K.
      Improved social interaction, recognition and working memory with cannabidiol treatment in a prenatal infection (poly I:C) rat model.
      ,
      • Zavitsanou K.
      • Lim C.K.
      • Purves-Tyson T.
      • Karl T.
      • Kassiou M.
      • Banister S.D.
      • et al.
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      ,
      • Gama C.S.
      • Canever L.
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      • Gubert C.
      • Stertz L.
      • Massuda R.
      • et al.
      Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: A study in adolescent rats with ketamine-induced model of schizophrenia.
      ). This suggests that compounds that do not depend on dopamine blockade may be viable alternatives to current antipsychotic drugs. However, as discussed above, antipsychotic-based interventions in ARMS cohorts have not been effective at preventing transition to clinical schizophrenia or improving symptoms long term (
      • Fusar-Poli P.
      • Davies C.
      • Solmi M.
      • Brondino N.
      • De Micheli A.
      • Kotlicka-Antczak M.
      • et al.
      Preventive treatments for psychosis: Umbrella review (just the evidence).
      ). This discontinuity in treatment efficacy between preclinical models and clinical cohorts suggests that 1) these models are not accurate representations of the neurobiology underlying transition to schizophrenia, 2) the behavioral phenotypes are inadequate reflections of clinical symptomology, or 3) the timescales at which animal models are assessed do not accurately reflect longer-term brain remodeling abnormalities in ARMS subjects. Some of these studies also revealed that chronic antipsychotic treatment during juvenile development can result in adverse outcomes in control animals (
      • Meyer U.
      • Spoerri E.
      • Yee B.K.
      • Schwarz M.J.
      • Feldon J.
      Evaluating early preventive antipsychotic and antidepressant drug treatment in an infection-based neurodevelopmental mouse model of schizophrenia.
      ,
      • Richtand N.M.
      • Ahlbrand R.
      • Horn P.
      • Stanford K.
      • Bronson S.L.
      • McNamara R.K.
      Effects of risperidone and paliperidone pre-treatment on locomotor response following prenatal immune activation.
      ,
      • Richtand N.M.
      • Ahlbrand R.
      • Horn P.
      • Tambyraja R.
      • Grainger M.
      • Bronson S.L.
      • McNamara R.K.
      Fluoxetine and aripiprazole treatment following prenatal immune activation exert longstanding effects on rat locomotor response.
      ), highlighting the need to find new, nontoxic prophylactics.

      Summary of Animal Models That Are Relevant to the Prodrome

      One convergent finding across models of the prodrome (Box 1) is evidence of dopaminergic dysfunction (and deficits in dopamine-related behaviors) that is generally (although not exclusively) apparent in adult, but not juvenile, animals. This robust finding is consistent with the postpubertal appearance of positive symptoms in patients, which are believed to be mediated by dopaminergic dysfunction (
      • McCutcheon R.A.
      • Abi-Dargham A.
      • Howes O.D.
      Schizophrenia, dopamine and the striatum: From biology to symptoms.
      ). Importantly, phenotypes relevant to negative and cognitive symptoms, as well as nondopaminergic neurobiological abnormalities, show greater variability between models. However, this may simply reflect the fact that these factors have been examined in fewer models. Further studies are clearly warranted to determine how the robust deficits in subcortical dopamine systems may interact with other brain regions and neurotransmitters.
      Current Animal Models Most Relevant to the Schizophrenia Prodrome
      • 1.
        Models specifically designed to recapitulate the dopaminergic dysfunction of the prodrome
        • a.
          Partial amphetamine-sensitization model: Uses a modified amphetamine-sensitization protocol to induce a prodromal level of dopaminergic dysfunction
        • b.
          Dopamine D2 receptor overexpression model: Uses a transgenic manipulation to increase levels of the D2 receptor in the striatum, reflecting striatal hyperdopaminergia
        • c.
          Enhanced dopamine in prodromal schizophrenia model: Uses a genetic construct to increase levels of dopamine-synthesizing enzymes in the nigrostriatal pathway
      • 2.
        Neurodevelopmental models of schizophrenia, retrospectively assessed at juvenile ages
        • a.
          Maternal immune activation models (e.g., PolyI:C [polyinosinic:polycytidylic acid] model)
        • b.
          Neonatal lesion models (e.g., neonatal hippocampal lesion models)
        • c.
          Prenatal neurotoxin (e.g., MAM [methylazoxymethanol acetate] model)
        • d.
          Genetic manipulation (e.g., 22q.11 deletion models)
        • e.
          Drug-induced (e.g., neonatal dizocilpine [MK-801] administration)

      Limitations and the Future of Animal Models for the Prodrome

      Limitations of current animal models for the prodrome are presented in Box 2.
      Limitations of Current Animal Models for the Prodrome
      • 1.
        Limits of the translatability of current behavioral tests to the attenuated symptoms of the prodrome
      • 2.
        Inadequate comparison of sex differences in the progression of neurobiological dysfunction
      • 3.
        a. Limited focus on behavioral symptoms/endophenotypes associated with transition, such as negative and cognitive symptoms and mismatch negativity
        • b.
          Difficulties of models of adolescent risk factors that are related to transition risk
      • 4.
        Limited longitudinal repeated testing, especially of neurotransmission/brain function with simultaneous behavioral studies

      Translatability of Behaviors

      A pervasive limitation of all preclinical models of schizophrenia is the difficulty in assessing positive-symptom phenotypes in rodents. Current tests—responsivity to psychotomimetic compounds and measures of sensory gating—likely do not accurately reflect the neurobiology underlying the positive symptoms of schizophrenia (
      • Kesby J.P.
      • Eyles D.W.
      • McGrath J.J.
      • Scott J.G.
      Dopamine, psychosis and schizophrenia: The widening gap between basic and clinical neuroscience.
      ). Novel signal detection tests may permit a more valid assessment of psychosis in rodents (
      • Schmack K.
      • Bosc M.
      • Ott T.
      • Sturgill J.F.
      • Kepecs A.
      Striatal dopamine mediates hallucination-like perception in mice.
      ); however, such tests can require extensive training and are therefore unsuited to time-sensitive analyses during adolescence. Regardless, there is a clear need to reassess the behavioral tasks used to represent the positive symptoms of schizophrenia. Diminished symptom severity as seen in the prodrome should also be reflected in preclinical models reflecting a phenotype magnitude intermediate between control animals and that observed in mature animals from the same model rather than simply the presence or absence of phenotype.

      Sex Differences

      Epidemiological studies suggest that the prevalence of schizophrenia is sexually dimorphic, with a male-to-female ratio of approximately 3:2 (
      • McGrath J.
      • Saha S.
      • Chant D.
      • Welham J.
      Schizophrenia: A concise overview of incidence, prevalence, and mortality.
      ). Men also show an earlier average age of onset (
      • Häfner H.
      From onset and prodromal stage to a life-long course of schizophrenia and its symptom dimensions: How sex, age, and other risk factors influence incidence and course of illness.
      ). This may be the consequence of altered maturational events that vary in timing dependent on sex (
      • Holland F.H.
      • Ganguly P.
      • Potter D.N.
      • Chartoff E.H.
      • Brenhouse H.C.
      Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males.
      ,
      • McCarthy M.M.
      Multifaceted origins of sex differences in the brain.
      ). These findings suggest that the neurobiology and course of the prodrome (and therefore also biological targets for intervention) may also be sex specific. Although a growing number of animal models include both male and female animals (Table S1), making this a standard practice would allow a robust assessment of sexually dimorphic neurobiological and phenotypic patterns in these models.

      Identifying Transition Likelihood

      Pinpointing markers of transition likelihood would be invaluable for early identification of ARMS subjects who will progress to schizophrenia. Although patterns of blood-based analytes can suggest those subjects most likely to transition to schizophrenia (
      • Chaumette B.
      • Kebir O.
      • Pouch J.
      • Ducos B.
      • Selimi F.
      • ICAAR study group
      • et al.
      Longitudinal analyses of blood transcriptome during conversion to psychosis.
      ,
      • Mongan D.
      • Föcking M.
      • Healy C.
      • Susai S.R.
      • Heurich M.
      • Wynne K.
      • et al.
      Development of proteomic prediction models for transition to psychotic disorder in the clinical high-risk state and psychotic experiences in adolescence.
      ), these tests are currently insufficiently sensitive and/or specific for diagnostic application (
      • Weickert C.S.
      • Weickert T.W.
      • Pillai A.
      • Buckley P.F.
      Biomarkers in schizophrenia: A brief conceptual consideration.
      ). Animal models may offer a solution; MIA-exposed adult animals can be clustered into two groups that show either the presence or absence of schizophrenia-relevant phenotypes (
      • Mueller F.S.
      • Scarborough J.
      • Schalbetter S.M.
      • Richetto J.
      • Kim E.
      • Couch A.
      • et al.
      Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation.
      ). Analyzing blood samples from these animals as juveniles may reveal putative biomarkers for transition.
      Factors including adolescent stress and cannabis use have been shown to increase the likelihood of transition to schizophrenia (
      • Johnstone E.C.
      • Ebmeier K.P.
      • Miller P.
      • Owens D.G.C.
      • Lawrie S.M.
      Predicting schizophrenia: Findings from the Edinburgh High-Risk Study.
      ). However, in preclinical models of these risks, the manipulation/treatment typically occurs during adolescence, with animals being assessed either in adulthood or immediately following cessation of the manipulation/treatment (normally in late adolescence). Such a study may therefore simply reflect the acute effects of the model, rather than its pervasive effects on neurobiology. For this reason, these studies were not included in this review. However, the neurobiological processes on which such factors act are likely crucial to schizophrenia onset.

      Technical Limitations

      Analysis of neurobiology alongside behavior is key to understanding the schizophrenia prodrome. Neuroimaging techniques are highly translatable and permit longitudinal analyses. However, these techniques are often limited in spatial and/or temporal resolution. Older in vivo techniques to examine neurotransmitter function cannot be used longitudinally owing to the tissue damage. Technical advances, such as the development of ultrafine fast scan cyclic voltammetry recording electrodes (
      • Schwerdt H.N.
      • Zhang E.
      • Kim M.J.
      • Yoshida T.
      • Stanwicks L.
      • Amemori S.
      • et al.
      Cellular-scale probes enable stable chronic subsecond monitoring of dopamine neurochemicals in a rodent model.
      ), genetically encoded sensors for dopamine signaling (
      • Patriarchi T.
      • Cho J.R.
      • Merten K.
      • Howe M.W.
      • Marley A.
      • Xiong W.H.
      • et al.
      Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors.
      ), and soft cortical “windows” into the brain (
      • Hayashi-Takagi A.
      • Araki Y.
      • Nakamura M.
      • Vollrath B.
      • Duron S.G.
      • Yan Z.
      • et al.
      PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence.
      ), may allow longitudinal analysis of schizophrenia-relevant neurobiology during the critical adolescent period.

      Conclusions

      A well-defined preclinical model of the schizophrenia prodrome (Box 3 and Figure 2) is now required to follow disease course, understand the neurobiology and circuits behind transition, and trial potential prophylactics. In addition, such a model may provide answers to currently intractable questions such as the following:
      • 1.
        Why do negative and cognitive symptoms precede the subacute psychotic symptoms of the prodrome?
      • 2.
        What is the neurobiological basis for the temporal differences in prodromal onset between men and women?
      • 3.
        What are the biomarkers that could predict transition?
      • 4.
        Is there a pharmacological agent or bioactive molecule that could delay symptom onset, diminish symptom severity, or ultimately prevent transition to the neurobiological and behavioral phenotypes relevant to schizophrenia?
      Criteria for an Optimal Animal Model of Relevance to the Prodrome
      • 1.
        Allows longitudinal testing of neurobiology and behavior
      • 2.
        Displays trajectory of normal juvenile/adolescent to abnormal adult brain circuits/cells/processes
      • 3.
        Shows schizophrenia-relevant phenotypes in adulthood
      • 4.
        Testing negative and cognitive symptoms as well as positive
      • 5.
        Includes both male and female animals
      • 6.
        Examines putative biomarkers (e.g., mismatch negativity response, inflammatory markers from blood)
      Figure thumbnail gr2
      Figure 2Summary of the ideal model of the schizophrenia prodrome. Animals (both male and female) would be assessed longitudinally for both behavioral and biological outcomes relevant to schizophrenia. Such an animal model would show phenotypes relevant to the positive symptoms of schizophrenia (drug-induced locomotion and impairments in PPI) in adulthood and attenuated expression of these phenotypes as juveniles. These animals would show cognitive deficits as both juvenile and adult animals. Based on clinical data, we expect these animals would show an attenuated MMN deficit as juveniles and robust MMN deficits in adulthood. The ideal animal model would also include progressive changes in brain structure, including accelerated cortical thinning, ventricular enlargement, enhanced synaptic pruning, and an increase in dopaminergic release in the dorsal but not ventral striatum. To assess putative biomarkers, blood samples would be acquired from these animals before any phenotype onset. A range of analytes (including neuroinflammatory markers) would then be correlated to adult outcomes (behavioral and/or neurochemical) to determine their value in predicting adult dysfunction. Finally, the ideal animal model of the prodrome would be used to trial interventions at a range of developmental stages to determine whether it is possible to rescue the abnormal maturation of the brain and prevent or delay onset of adult phenotypes. CC, cerebral cortex; DS, dorsal striatum; LV, lateral ventricle; MMN, mismatch negativity; PC, personal computer; PPI, prepulse inhibition.
      Data from brain imaging modalities and emerging clinical observations from the ARMS subject groupings will help to refine future animal models with relevance to the schizophrenia prodrome in an iterative cycle. We must continue to improve animal models of psychiatric disorders while considering the adage from statistician George Box: “all models are wrong, but some are useful” (
      • Box G.E.P.
      • Draper N.R.
      Empirical Model-Building and Response Surfaces.
      ).

      Acknowledgments and Disclosures

      Funding for this work came from the National Health and Medical Research Council (Grant No. APP1124724 [to DE]).
      We acknowledge Suzy Alexander for assisting with the manuscript figures.
      The authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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      Linked Article

      • Limitations and Value of Animal Models of Relevance to the Schizophrenia Prodrome
        Biological Psychiatry: Global Open ScienceVol. 3Issue 1
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          In the current issue of Biological Psychiatry: Global Open Science, Petty et al. (1) discuss animal models of relevance to the schizophrenia prodrome. These models are essentially rodent models of schizophrenia in which the animals are assessed during adolescence and early adulthood. This is the period in which brain structures and networks are changing in both rodents and humans and is the age range of highest risk for onset of schizophrenia in humans. How useful are these animal models for research and clinical work in humans? As I discuss herein, both animal and human factors affect their usefulness.
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