Schizophrenia Research Forum: Animal Models
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Animal Models:Developmental
Name DA-related behavior Gating Cognitive behavior Social behavior Molecular and/or Morphological Signature Response to APD
Monkey Fetal Irradiation     Impaired working memory   Mid-gestational irradiation decreases both gray and white matter in frontal cortex.  
Mouse Prenatal Immune Challenge: Human Influenza Virus Decreased open field exploration Impaired PPI   Impaired social interaction Reduced reelin expression in cortex layer 1; increased pyramidal cell density; cortical and callosal atrophy; reduced 5-HT levels in cerebellum atrophy; altered expression of myelination genes in the cerebellum; reduced 5-HT levels in cerebellum; increased 5-HT2A receptor expression in frontal cortex Clozapine and chlorpromazine increase PPI hyper-reversal of PPI deficit
Mouse Prenatal Immune Challenge: PolyI:C (delivery timing varies) No change in total distance traveled in open field but reduced center exploration; increased response to amphetamine and MK-801 (emerges after puberty; not rescued by cross-fostering) Disrupted PPI (post-puberty; deficits not rescued by cross-fostering) Reduced escape latency in Morris water maze; impairment in novel object recognition memory; deficits in latent inhibition (post-puberty; deficits not rescued by cross-fostering); electrophysiology: reduced theta oscillation generated in the CA1 area of the hippocampus Reduced social interaction Increased DA turnover and reduced binding to D2 receptors in striatum; reduced reelin- and parvalbumin- expressing neurons in PFC; reduced DA levels and D1 receptors in PFC; increased TH expression in striatum; reduced density of cerebellar Purkinje cells; delayed myelination of hippocampus; reduced parvalbumin-expressing neurons in the hippocampus; enlargement of lateral ventricles; impaired synaptic development of upper-layer neurons Disrupted PPI was improved by clozapine and chlorpromazine; deficits in latent inhibition and novel object recognition memory were improved by clozapine but not haloperidol; deficits in Morris water maze were improve by clozapine
Mouse Prenatal Restraint Stress Increased novelty induced locomotor activity; enhanced MK-801induced locomotion Impaired PPI Deficits in object recognition memory and contextual fear conditioning Reduced social interaction Abnormal Purkinje cell growth and dendritic atrophy; glial deficits in the hippocampus (female specific); over-expression of DNMTs mRNA in the frontal cortex; decreased GAD67, reelin, and mGlu2 and mGlu3 receptor protein levels in the frontal cortex; altered neuronal migration Clozapine reversed deficits in PPI and social interaction; increased locomotive response to MK-801 was attenuated by clozapine; phenotypic rescue with mGluR2/3 agonist or valproic acid
Mouse Prenatal Variable Stress (GD1-7)     Altered learning and memory during a modified Barnes maze task (sex specific; timing specific)   Increased plasma glucocorticoid levels following stress; altered expression of glucocorticoid receptor expression in the hippocampus; dysmasculinization of offspring and second generation offspring (paternal stress lineage) via epigenetic programming  
Rat 24-Hour Maternal Deprivation on Postnatal Day 9   Disrupted PPI, Effect develops after puberty.     Males only: neuronal degeneration and increased GFAP+ cells in cerebellum; neuronal degeneration and increased astrocytes in hippocampus Both sexes: altered cannabinoid receptor expression in hippocampus; increased plasma glucocorticoid levels; increased levels of 5- HT in the prefrontal cortex, hippocampus, and striatum (some changes sex dependent); increased levels of DA in the prefrontal cortex and striatum Haloperidol reverses PPI deficit.
Rat Antimitotic Agent (MAM or AraC) Enhanced response to amphetamine and MK-801 (post-puberty) Disrupted PPI (post-puberty) Learning deficits in Morris water maze, object recognition, and attentional set-shifting; no change in 5-choice serial reaction time task Decreased social interaction (deficit present prior to puberty) Reduced hippocampal volume; alterations of NMDAR protein levels and function in the hippocampus; increased neuron density in prefrontal cortex; enhanced NAc DA release to amphetamine; increased firing of dopaminergic neurons; enlarged lateral and third ventricles Increased response to MK-801 was attenuated by risperidone, haloperidol, and clozapine
Rat Isolation Rearing Enhanced amphetamine-induced locomotion and DA release (strain-dependent) Disrupted PPI (strain-dependent) Performance on Morris water maze and T-maze appears normal Impaired novel object recognition, attentional set-shifting, and performance on Morris water maze Increased social interaction and aggression (males); impaired social recognition Reduced PFC volume (neuron # unchanged) and GAT-1 expression; altered accumbal protein expression (some correlated with PPI deficits); reduced accumbal dendritic length and spine density; altered NMDA receptor mRNA and protein expression in the hippocampus and prefrontal cortex; enhanced amplitudes of hippocampal voltage-dependent transient outward K+ currents Raclopride reversed PPI deficit
Rat Maternal Malnutrition Enhanced amphetamine- but not MK-801-induced locomotion and apomorphine-induced stereotopy; (females only with post-pubertal onset) Disrupted PPI (females only with post-pubertal onset)     Increases in NMDA receptor binding (sex- and region-specific); increased DA receptor binding and decreased DA transporter binding in striatum (females only)  
Rat Neonatal Immune Challenge: Borna Disease Virus Enhanced novelty induced locomotor activity in Fisher rats; enhanced amphetamine-induced locomotion Disrupted PPI in Fisher rats Reduced social interaction   Impairs BDNF synaptogenesis; prefrontal cortex thinning; loss of cerebellar Purkinje neurons; increased norepinephrine and 5-HT levels in cortex and cerebellum (post-pubertal)  
Rat Placental Insufficiency/Birth Insults Enhanced amphetamine-induced locomotion and accumbal dopamine release Disrupted PPI (post-pubertal onset) Performance on Morris water maze and T-maze appears normal   Reduced DA release in PFC, increased DAT in NAc (basal), decreased DA receptor expression; reduced dentate granule cells; region- and age-specific alterations in dendritic spine development; altered expression of presynaptic genes; decreased caudate-putamen volume PPI deficits reversed by clozapine
Rat Prenatal Immune Challenge: LPS Increased amphetamine-induced locomotion Enhanced acoustic startle; disrupted PPI (worse in males) Impaired object recognition (post-puberty) Reduced social interaction, possibly due to increased anxiety Reduced dendritic complexity in PFC and hippocampus; increased accumbal DA and striatal DOPAC; elevated serum and fetal brain cytokine levels; altered frontal synaptophysin expression; reduced parvalbumin-expressing neurons in the hippocampus; down regulated expression of several genes involved in neurogenesis and neuronal migration; (direction of some changes are age-dependent) PPI deficit and elevated serum cytokines both reversed by haloperidol
Rat Prenatal Immune Challenge: PolyI:C (delivery timing varies) Increased response to amphetamine (emerges after puberty); in moms that lost or gained little weight offspring showed attenuated hyperactivity in response to MK-801 Disrupted PPI (possibly sex dependent) Disrupted latent inhibition (post-puberty); impaired novel object recognition; classical fear conditioning, active avoidance, water maze and discrimination learning appear normal   Amphetamine-induced DA release increased; increased hippocampal pyknotic cells Deficit in latent inhibition was improved by clozapine and haloperidol; altered response to amphetamine was attenuated by adolescent treatment with fluoxetine and aripiprazole
Rat Prenatal Restraint Stress Increased novelty induced locomotor activity No disruption in PPI Memory deficits during Y maze and radial arm maze; no apparent deficits in latent inhibition, may or may not show spatial memory defict in water maze task   Increased expression of D2-like and NMDA receptors in the frontal cortex and hippocampus; prolonged corticosterone stress response and decreased expression of central corticosteroid receptors (sensitive to cross-fostering); increased basal dopamine and decreased noradrenaline output in the nucleus accumbens; decreased basal noradrenaline output in the prefrontal cortex; apical dendritic atrophy and altered spine density in the hippocampus; decrease neurogenesis in hippocampus Maternal fluoxetine treatment improves hippocampal neurogenesis and reverses anxiety behaviors in stressed offspring
Rat Prenatal Variable Stress Increased response to amphetamine and PCP with post-pubertal onset Disrupted PPI and N40 Impaired object and social recognition; deficits in Morris water maze; impaired cued and contextual fear conditioning; impairment in sustained attention and inhibitory response control Impaired social interaction present in adolescent and adult rats; reversal by oxytocin; no effect of cross-fostering NMDA, GABAergic and presynaptic protein dysregulation; reduced hippocampal neurogenesis and hippocampal volume; decreased BDNF protein expression in the hippocampus (strain dependent); altered pattern of apical dendritic maturation of pyramidal neurons (males only) Social interaction deficit not improved by haloperidol
Rat Prenatal Vitamin D Insufficiency Enhanced MK-801induced locomotion; enhanced amphetamine-induced locomotion (females only) No disruption in PPI   No deficit in social behavior Enlarged lateral ventricles; thinned cortex; altered brain expression of proteins involved in mitochondrial function, calcium homeostasis, and synaptic plasticity; decreased neurogenesis Haloperidol ameliorated effects on neurogenesis