Schizophrenia Research Forum: Animal Models
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Animal Models:Genetic
Name DA-related behavior Gating Cognitive behavior Social behavior Molecular and/or Morphological Signature Response to APD
15q13.3 Microdeletion, Df(h15q13)/+   Auditory processing deficits Impaired long-term spatial reference memory Increased aggression following mild stress Altered neuronal activity in acute seizure assays; decreased theta frequency in the hippocampus and PFC  
22q11.2 Deletion Model-Df(16)A Hyperactive in novel environment PPI deficit Impaired fear conditioning; spatial learning deficit   Reduced dendritic spines in HPC, reduced hippocampal-prefrontal synchrony, Dgcr8 haploinsufficiency, disruption of synaptic transmission at thalamocortical glutamatergic projection in the auditory cortex Thalamocortical projections sensitive to antipsychotics
22q11.2 Deletion Model-Lgde1 Normal activity in open field PPI deficit Normal fear conditioning   Disrupted cortical neurogenesis and interneuron migration  
22q11.2 Deletion-Df1   Disrupted PPI Impaired cognitive function   Haploinsufficiency of Tbx1 and Gnb1l responsible for PPI deficit  
Adenosine Kinase Transgenic Reduced locomotor response to amphetamine; enhanced locomotor response to MK-801   Learning deficits in Morris water maze and Pavlovian conditioning   Overexpression of adenosine kinase; reduced levels of adenosine in brain  
AKT1 KO Normal activity in open field No baseline PPI in males, baseline PPI deficit in females (Chen; Emamian did not find PPI deficit in either sex at baseline); PPI deficit caused by amphetamine No impairment in spatial learning     Antipsychotics did not normalize PPI in females, but GSK inhibitors did
Alpha-CaMKII KO, Heterozygous Increased locomotor.   Deficits in working memory. Increased aggressive behavior. Impaired neuronal development in the dentate gyrus.  
AMPA GluR4 KO Normal activity in open field; increased sensitivity to MK-801 Reduced startle response; PPI deficits Impaired spatial learning, but enhanced performance in reversal learning Increased social interaction with familiar cagemate    
AMPAR GluR1 Subunit KO Hyperactive, no effect of MK-801 on locomotor behavior PPI deficit Disrupted spatial working memory Disorganized social behaviors Slowed extracellular DA clearance in striatum Anxiety prone; Hyperactivity reversed by haloperidol
Aph1B/C KO Enhanced hyperactivity in response to amphetamine PPI deficits, hypersensitive to MK-801 (increased PPI deficits) Impaired working memory on Morris water maze   Enhanced DA turnover in ventral striatum; gamma-secretase dependent cleavage of Nrg1 is impaired Haloperidol and clozapine reverse PPI deficits
Apomorphine Susceptible Rat Enhanced locomotor response to novel open field Disrupted PPI and diminished latent inhibition; Visual and acoustic PPI deficits; Sprague-Dawley rats more sensitive t     Preferential mobilization of NMDAR NR1 subunits in D1R containing neurons of the nucleus accumbens  
BACE1 KO Increased novelty-induced hyperactivity; hypersensitivity to locomotor effects of MK-801 PPI deficits Working memory deficits; impaired in inhibitory avoidance task Alterations in social recognition Impaired processing of NRG1; decreased spine density and mature spines in CA1 Clozapine attenuates novelty-induced hyperactivity and normalizes PPI deficits
Beta-Arrestin 2 KO Decreased locomotor response to amphetamine       Normal DARRPP-32 phosphorylation after amphetamine  
Brattleboro (Vasopressin-Deficient) Rat Hyperactive in novel setting Increased acoustic startle and decreased PPI   Impaired social discrimination Point mutation in gene for vasopressin; decreased dopamine concentration in frontal cortex PPI deficit reversed by acute clozapine and risperidone; chronic but not acute haloperidol reverses deficit
Calcineurin A-gamma KO Enhanced response to amphetamine Disrupted PPI and latent inhibition Disrupted PPI and latent inhibition Impaired social interaction Inducible KO  
Cannabinoid Receptor 1 (CB1) KO Decreased PCP-induced locomotion     No effect on social interaction    
Cannabinoid Receptor 2 KO Hypoactive in open field; enhanced hyperactivity in response to cocaine PPI deficit Impaired memory consolidation     PPI deficit improved by risperidone
Chakragati (ckr) Circling, hyperactive PPI and latent inhibition deficits   Reduced social interactions Enlarged ventricles  
Complexin I KO Decreased amphetamine-induced locomotion   No cognitive deficits in two-choice swim tank Social deficits; no preference for social novelty; no aggressive behavior in resident-intruder paradigm    
Complexin II KO     Decreased LTP; reduced Morris water maze performance only after stress      
COMT KO No potentiation of amphetamine-induced locomotion Absence of deficits in PPI; increased startle responses Impaired recognition memory in heterozygous; COMT KO males had enhanced performance in working memory task, attentional set shifting task, and 5CSRTT; COMT KO females had working memory deficits No deficit in sociability or social novelty in KO or hets; however males had increased aggressive behavior Increased DOPAC; D1 and D2 unchanged; sexually dimorphic changes in dopamine levels in the frontal cortex Increased anxiety
COMT Val Transgenic   Decreased startle response; PPI not effected Deficits in object recognition, working memory and attentional set-shifting   Increased levels of CaMKII in PFC; displayed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power Nicotine restored normal event-related activity
D2 Receptor Transient Overexpression Hyperactive   Impaired working memory   Overexpression of D2 receptors in striatum  
D-Amino Acid Oxidase Deficient ddy/DAO Strain Hypoactive in open field; attenuated response to PCP Increased startle amplitude; no PPI deficit (Almond; enhanced PPI found by Zhang)        
DBA/2   Disrupted N40 gating and PPI     Decreased levels Glu, tau and GABA in hippocampus Phenotype reversed by a7-nicotinic and α4β2 receptor agonist; by olanzapine via alpha7-nicotinic receptor; by gestational choline supplementation; by baclofen and clozapine
Densin-180 (LRRC7) KO Hypoactive in familiar setting; hyperactive in novel setting PPI deficits Impaired spatial memory; Impaired novel object recognition Impaired nest-building; increased aggression Impaired LTD; altered morphology of dendritic spines  
DISC 129S6/SvEv (25-bp Deletion in Exon 6)     Working memory deficit   DISC1 mutation; deficit in hippocampal short term plasticity; altered organization of neurons in dentate gyrus  
DISC1 Dominant-Negative Transgenic Hyperactive in open field No PPI deficit No impairment in working memory in T-maze or spatial learning in water maze Impaired social interaction Decreased cortical parvalbumin-containing cells  
DISC1 L100P Missense Mutation Increased locomotor activity; enhanced response to amphetamine Disrupted PPI; Decreased startle amplitude Working memory impaired in T-maze; normal spatial learning in water maze   Reduced brain volume; reduced dendritic spine density; increased striatal dopamine receptors Clozapine and haloperidol reversed PPI deficit; genetic inactivation of GSK-3alpha improves PPI, hyperactivity and dendritic spine abnormalities
DISC1 Mutant (Exon 2/3 Deletion) Normal activity in open field PPI deficit No impairment in working memory or novel object recognition Increased social interaction No morphological changes; altered threshold for LTP  
DISC1 Transient Knockdown in PFC (In Utero) Normal spontaneous locomotion; hypersensitive to methamphetamine PPI deficits in adults but not juveniles Impairment in novel object recognition test   Reduced dopamine concentration in PFC; Reduced parvalbumin-positive interneurons in PFC PPI deficits normalized by clozapine; impairment in novel object recogntion test normalized by clozapine
Disc1tr (Truncated, Exons 1-8) Increased immobility Impaired conditioning of latent inhibition     Enlarged ventricles; reduced Parvalbumin neurons in hippocampus & mPFC  
Disheveled 1 KO   Disrupted PPI   Impaired social interaction    
Dopamine Transporter KO Increased DA and decreased D1R, D2R, hyperactive Disrupted PPI Impaired adaption to environmental changes in Morris water maze Impaired social behavior Decreased LTD in hippocampus More aggressive; impairments in Morris water maze reversed by haloperidol and acute nicotine treatment; LTD reversed by haloperidol
Dysbindin-1, Sandy (sdy) DBA/2J Delayed hyperactivity in novel environment; less active in open field   Object recognition deficit; impaired long-term memory retention and working memory Decreased social interaction DTNBP1 mutation with lack of dysbindin protein; increase in DA metabolism in different brain regions; reduced snapin in hippocampus; decreased DA levels in cortex, hippocampus and hypothalamus; altered kinetics of transmitter release  
Dysbindin-1, Sandy C57BL/6J Increased baseline locomotor activity; normal amphetamine-induced locomotor activity Increased startle and prepulse inhibition Acquired working memory task faster than wt but had impaired working memory under challenging/stressful conditions; cognitive deficits in operant tasks possibly due to increased impulsive and compulsive behavior   Decreased CamKII in mPFC; increased D2 receptors in PFC; decreased excitability if FS GABAergic interneurons in PFC and striatum; pyramidal neurons in MPFC layer II/II were hyperexcitable at baseline but less sensitive following D2 stimulation  
ErbB2/B4 CNS KO Normal locomotor behavior PPI deficit in males only   Increased aggression Reduced dendritic spine density Clozapine reduced behavioral changes
ErbB4 KO Reduced spontaneous activity; hyperactivity in open field   Reduced Morris water maze learning   Reduced myelination, enhanced DA receptor expression  
FEZ1 KO Hyperactive; enhanced response to MK-801 and methamphetamine       Increased methamphetamine-induced DA release in nucleus accumbens  
FGFR1 Catecholaminergic Neuron Targeted Knockout Hyperactive in open field Increased startle response; PPI deficits   Decreased social interaction Increased striatal dopamine metabolites PPI deficit reversed with flupenthixol, quetiapine and clozapine; clozapine did not reduce hyperactivity
Fut8 (alpha1,6-fucosyltransferase) KO Hyperactive in novel setting PPI deficit Impaired working memory Decreased social interaction   Hyperactivity reduced by haloperidol
G72Tg Transgenic Normal activity in open field; impaired motor coordination in rotarod and beam-walking tests; enhanced locomotor response to PCP PPI deficit   Normal social interaction; increased aggression in males   PPI deficit reversed with haloperidol
GABAA alpha3 Receptor KO Spontaneous locomotor activity slightly increased but not after amphetamine Disrupted PPI       PPI defect improved by haloperidol Rx
Galphas Overexpression in Forebrain Hyperlocomotion PPI deficit Impaired hippocampus-dependent learning and memory retrieval   Enlarged ventricles PPI deficits reversed by haloperidol and rolipram
GAP-43 KO Hyperactive in open field, reduced anxiety Disrupted PPI        
GDI1 Knockout     Impaired short-term memory Diminished social behavior   Less aggression
GLAST (EAAT1) KO Locomotor hyperactivity in novel environment; exaggerated hyperactivity in response to MK-801         Phenotype normalized by haloperidol and mGlu2/3 agonist
Glutamate Carboxypeptidase II (GCP II) Heterozygous KO Hyperactive in open field No PPI deficit Mild impairment in spatial working memory Decreased social interaction    
Glutamate-Cysteine-Ligase Modifier (GCLM) KO Hyperactive in novel setting (Kulak; not found by Cole); potentiated locomotor response to amphetamine No PPI deficits (Cole); mild PPI deficit (Kulak) Normal spatial working memory and spatial learning Abnormal social preference (Kulak) Glutathione deficiency  
Glycine Transporter KO Locomotor response to psycho-stimulants same as wild-type Reduced sensitivity to amphetamine to disrupt PPI but more MK-801 induced disruption Improves memory retention   Increased NMDA receptor expression and function  
Grin D481N/K483Q Combined Point Mutation Nonhabituating hyperactivity Increased startle response, no PPI deficit Impaired spatial learning Impaired nest building Reduced NMDAR glycine affinity; reduced LTP in hippocampus Clozapine and haloperidol did not reduce hyperactivity
Grin1D481N NR1 Point Mutation   Persistent latent inhibition; no PPI deficit; increased startle reactivity Spatial recognition impairments Social approach deficits Reduced NMDAR glycine affinity; reduced LTP in hippocampus Phenotype reversed by D-serine treatment as well as D-amino acid oxidase gene deletion
GSK-3beta Knockout   Disrupted PPI correlates with enzyme activity; no PPI disruption (Bersudsky)        
HB-EGF Forebrain-Specific KO Hyperactive in novel setting and home cage PPI deficits Impaired novel object recognition Decreased social interaction Reduced dopamine, serotonin, PSD-95 and NR1 in prefrontal cortex Hyperactivity reduced by haloperidol and clozapine; PPI deficits reduced by risperidone and clozapine; clozapine but not haloperidol improved social behavior
hDISC1 Mutant, Inducible Spontaneous hyperactivity   Deficient spatial memory in females Alterations in social interaction Attenuation of neurite outgrowth in cortical neurons; enlarged ventricles  
Homer1 KO Hypoactive; enhanced locomotor behavior to MK-801 and methamphetamine Disrupted PPI (Szumlinski; not found by Jaubert) Decreased radial arm maze performance Increased social interaction; increased aggression in heterozygotes; impaired nest-building Decreased glutamate release in PFC following cocaine Rx  
Imprinting Center Deletion Model of PWS Hypoactive in open field Increased acoustic startle; PPI deficit Impaired attention in serial reaction time task      
Insulin Receptor KO   Decreased startle amplitude     Decreased insulin receptor and Akt signaling; reduced phosphorylated GSK-3 Clozapine alleviates insulin resistance
LPA1 Receptor KO Reduced activity in novel setting; impaired habituation PPI deficit Impaired spatial working and reference memory   Abnormal expression and phosphorylation of NMDA and AMPA subunits  
LRRTM1 KO Hypoactive in novel settings   Deficit in spatial memory in water maze task Deficit in social recognition Reduced hippocampal volume and synaptic density  
MCH KO Increased basal locomotor activity; hypersensitive locomotor response to d-amphetamine          
mGluR1 Knockout   Disrupted PPI       Not reversed by raclopride
mGluR5 Knockout Abnormal locomotor patterns; increased sensitivity to hyperlocomotive effects of MK-801 Disrupted PPI Short term spatial memory deficits     APD not effective; clozapine reversed PPI deficit and ameliorated locomotor disruption (Gray)
Midkine (Mdk) KO Normal activity in open field PPI deficit Normal novel object recognition Decreased social contacts, but increased time per contact Reduced dopamine, D1R and D2R in striatum  
Mutant Human DISC1 (hDISC1) Spontaneous locomotor activity (males only)   Impaired spatial memory (females only) Altered social interaction (males only) Enlarged lateral ventricles; decreased cortical dopamine; reduced parvalbumin-positive neurons in the cortex  
NCAM-180 KO   Disrupted PPI, no changes induced by apomorphine Rx       Increase lateral ventricle size
NCAM-EC Overexpressing Hyperactive in open field; enhanced response to amphetamine and MK-801 PPI deficit Decreased LTP in PFC, normal LTP in HPC; impaired working memory Normal sociability Abnormal GABAergic interneurons PPI deficit reversed by clozapine but not haloperidol
Neuregulin 1 Heterozygous Knockout of EGF-Like Domain Hyperactive in open field (Duffy; not replicated by Ehrlichman or Moy); normal exploratory behavior No PPI deficit Normal novel object exploration Decreased social interaction (Ehrlichman; increased sociability but decreased social novelty preference found by Moy)    
Neuregulin 1 Heterozygous Knockout of Ig-Like Domain Normal activity in open field   Impaired latent inhibition     Clozapine reduced activity in open field
Neuregulin 1 Hypomorph (Transmembrane Domain) Hyperactive in open field test Disrupted PPI No impairment in spatial learning or working memory but diminished social recognition memory Increase in dominance related and aggressive behavior depending on environment Reduced NMDA receptor activity; increased serotonin 2A receptors and serotonin transporters in CNS Open field behavior reversed by clozapine but not PPI
Neuregulin 1 Overexpression Hyperactive in novel setting (Kato; not found by Deakin); impaired performance on rotarod Increased startle response and PPI deficits (Deakin, not found by Kato) Impaired context-dependent fear conditioning Impaired nest-building; decreased social interaction, increased aggression    
Neuregulin 1 Type II Hypomorphic Rat Normal activity in open field; impaired habituation in males, enhanced habituation in females Enhanced habituation; PPI deficit in females Deficits in visuospatial learning and memory; altered fear conditioning (cued)   Increased basal corticosterone levels  
Neurexophillin 3 KO Reduced rotorod performance Disrupted PPI but increased startle response     Expressed in Cajal-Retzius cells  
Neuropeptide Y Receptor 2 (Y2) KO Hyperactive in open field PPI in males Normal working memory and reference memory Increased social interaction in males    
Neuropeptide Y Receptor 1 (Y1) KO   Reduced startle response; impaired habituation; no PPI deficit        
Neurotensin 1 Receptor KO Hyperactive in open field; no effect of PCP on locomotor activity; enhanced hyperactivity in response to amphetamine No PPI deficit (Feifel)     Decreased glutamate and NMDA-2A subunit concentration; increased striatal dopamine  
Neurotensin 2 Receptor KO Hyperactive in open field (Liang; not found by Feifel) Enhanced PPI in males     Increased striatal dopamine  
NgR1 KO Mildly hypoactive Strain-background dependent absence of PPI Reduced spatial working memory      
Nitric Oxide Synthase KO Hyperactive in novel setting No PPI deficit Impaired spatial memory; impaired contextual fear conditioning Increased social interaction; reduced social novelty preference    
NMDA NR1 Receptor Hypomorph Enhanced response to amphetamine Disrupted PPI   Impaired social interaction 95% reduction in NR1 expression Behaviors improved by APD
Nogo-A KO Enhanced hyperactivity in response to amphetamines PPI deficit Perseverative behavior; normal spatial learning      
nPAS 1/3 KO Enhanced open field locomotion Disrupted PPI Decreased social recognition   Reduced reelin interneurons  
Nrg1 Type III Targeted Disruption, Heterozygous   PPI deficits Impaired short-term memory   Enlarged ventricles; decreased dendritic spine density on subicular neurons PPI deficits reversed by chronic nicotine treatment
Nurr1 Heterozygous KO Hyperactive in novel environment and also after amphetamine; enhanced response to MK-801 Disrupted PPI in males but not females Decreased emotional memory; intact spatial memory No social interaction deficit Reduced DA turnover in striatum; Increased DA turnover in PFC Haloperidol reverses spontaneous hyperactivity
Oxytocin and Oxytocin Receptor KO   PCP treatment induces large deficits in PPI   Impaired social discrimination   More aggressive
P35 (CDK5 Activator) Heterozygous KO No locomotor abnormalities PPI deficit in females, not males Reversal learning impaired in females Social interaction deficit in males    
PACAP KO Hyperactive in open field PPI deficit   Reduced social interaction   Hyperactivity reduced with risperidone; PPI deficit reversed by risperidone; social interaction deficit and hyperactivity reduced when animals raised in enriched environment
PDE4B KO Reduced baseline motor activity; exaggerated locomotor response to amphetamine Decreased PPI No deficit in Morris water maze   Decreased striatal DA and 5-HT activity  
PDGFR-beta KO   PPI deficit Impairment in fear conditioning Decreased social interaction Reduced GABAergic neurons in HPC, PFC and amygdala  
PGE2 EP2 KO Normal activity in open field PPI deficit Normal spatial memory; impaired fear conditioning Impairment in social habituation    
Phosphodiesterase 1B KO Enhanced behavioral response to methamphetamine   Morris water maze performance impairment   Increased DARPP-32 phosphorylation  
PLC-beta1 KO Hyperactive Sensorimotor gating deficits Memory impairment and lack of acquisition on hippocampal-dependent fear conditioning task Abnormal social behavior   Clozapine (McOmish) and haloperidol (Koh) rescues sensorimotor deficits
Proline Dehydrogenase (ProDH) KO Reduced open-field behavior, enhanced response to amphetamine and MK801 Diminished PPI     COMT, calcineurin upregulation, reduced D1 and DARPP-32 expression  
Reeler, Heterozygous Enhanced mesolimbic dopamine Cross-modal PPI deficits, no unimodal PPI deficit Decreased working memory; no decrease in prefrontal cortex dependent task Impaired social interaction Reduced GAD 67, increased DNA methylation; increased truncated TrkB receptor, decreased BDNF/TrkB signaling in frontal cortex  
Regulator of G-protein Signaling 4 (RGS4) KO   Subtle PPI deficits Impaired working memory      
Retinoic Acid Receptor KO Reduced open field locomotion       Reduced D1R and D2R  
Rictor KO   PPI deficit     Reduced phosphorylation of AKT1; reduced dopamine in frontal cortex  
RIM1alpha KO Hyperactive in novel setting; enhanced response to MK-801 PPI deficits   Decreased social interaction    
Selectively Bred Low PPI Wistar Rat Reduced motivation PPI deficits, reduced startle habituation Enhanced perseverative behavior Decreased social interaction    
Serine Racemase 1st Exon KO Hyperactive   Impaired spatial memory; disrupted order of events representation No social interaction deficit Lack ability to produce D-Serine; altered glutamatergic neurotransmission; abnormal dendritic morphology  
SNAP 25 Mutant Deficit in exploratory behavior PPI deficit   No social interaction deficit    
SNAP 25 Overexpression Normal locomotion in open field No PPI deficit Impaired spatial learning in water maze; impaired contextual fear conditioning   Overexpression of SNAP 25 in hippocampus of adult rat  
Sp4 Hypomorphic   PPI deficit Impaired spatial learning; impaired LTP   Hippocampal vacuolization; abnormal development of dentate gyrus; reduced levels of NMDA-NR1 but not NR2A or NR2B  
SREB2 Transgenic   PPI impairments Contextual memory deficits in fear-conditioning task Decreased social interaction Overexpression of SREB2 (GPCR85) in forebrain; Reduced brain weight, increased ventricular volume  
STOP KO Hyperactive; alterations in dopaminergic neurotransmission in the mesolimbic pathway Disrupted PPI Deficits in short term memory and spatial learning; deficits in long-term memory and object recognition Deficits in social learning and recognition Enlarged ventricles; reduced volume of cortex and diencephalon; hypoglutamatergic activity PPI deficit not blocked by clozapine
Synapsin II KO   PPI deficit   Social interaction deficit    
Synapsin III KO Hyperactivity in open field PPI deficit Normal spatial learning; object recognition deficit; Abnormal fear conditioning      
SynGAP Heterozygote Hyperactive; increased stereotype in open field Increased acoustic startle response; reduced PPI Apparent working memory impairment in T-maze alternation task; Decreased fear conditioning Impaired social memory; deficit in social interaction   Clozapine improves hyperactivity
Tcf4 Overexpressing Transgenic Normal activity in open field PPI deficit Normal spatial learning in water maze task; impaired fear conditioning      
Trace Amine 1 Receptor KO Enhanced locomotor response to amphetamine Disrupted PPI     Increased psychostimulant-induced DA release  
Urokinase Plasminogen Activator Receptor KO (Plaur)     Impaired reversal learning   Reduced parvalbumin-positive interneurons in anterior cingulate and orbitofrontal cortex; reduced levels of HGF/SF Postnatal supplementation with HGF/SF normalizes reversal learning impairment
Vasopressin 1a Receptor KO     Decreased social recognition     Phenotype rescued by increase V1a expression in lateral septum
Vasopressin 1b Receptor KO Reduced PFC DA Disrupted PPI Impaired novel object recognition Decreased social interest; decreased social novelty preference; Impaired social recognition   Atypical APD improve PPI but not haloperidol
YWHAE Heterozygous KO Normal activity in open field No PPI deficits Mild deficit in spatial working memory, no impairment in reversal learning Normal social interaction 50% reduction of 14-3-3epsilon protein expression