Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

Table 1

Summary of evidence for gene, environment, and gene × environment effects in mutant models for selected genes associated with schizophrenia.

Gene target	Environmental exposure	Reference(s)	Impact on schizophrenia-relevant; behavioural endophenotypes			Use of preventative or rescue strategy
			Genetic manipulation	Environmental manipulation	Gene × environment
NRG1	Prenatal Poly I:C	[92]	Decreased social novelty preference and PPI; sex-specific (females only) decrease in working memory	Disruption of working memory and PPI	Decreased sociability in Poly I:C × WT mice only; sex-specific decrease in alternation (i.e., working memory) following Poly I:C treatment was attenuated in female NRG1 mutants	—
NRG1	Acute Δ-9 THC during adulthood	[128, 129]	Increased novelty-induced activity; decreased anxiety in the elevated plus maze and light-dark test; increased c-fos expression in the lateral septum and nucleus accumbens	Decreased novelty-induced activity; increased anxiety in the elevated plus maze; enhanced PPI; decreased social interaction; increased c-fos expression in the dorsolateral part of the bed nucleus of the stria terminalis and central nucleus of the amygdala	Increased sensitivity to locomotor suppressant effects of THC in NRG1 mutants; greater PPI enhancement in NRG1 mutants; greater increase in c-fos expression in the dorsolateral part of the bed nucleus of the stria terminalis and central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus in NRG1 mutants	—
NRG1	Subchronic CP 55, 940 [CB1R agonist] during adulthood	[131]	Increased novelty-induced activity	Decreased novelty-induced activity; increased anxiety in elevated plus maze and open field	Increased tolerance to CP55,940-induced anxiolytic and locomotor suppressant effects in NRG1 mutants; increased c-fos expression in lateral septum in treated NRG1 mutants	—
NRG1	Subchronic Δ-9-THC during adolescence	[132]	Increased novelty-induced activity	Decreased novelty-induced activity	Decreased anxiogenic effects of THC in NRG1 mutants; decreased social investigative behaviours in WT only; disruption of PPI in THC-treated NRG1 mutants	—
NRG1	Subchronic cannabidiol during adulthood	[136]	Increased novelty-induced activity; disrupted PPI; decreased 5- receptor binding in substantia nigra	Enhanced PPI after acute cannabidiol; increased social interaction following chronic cannabidiol	Decreased sensitivity to anxiolytic effects of cannabidiol in mutants; selective enhancement of social interaction and PPI in NRG1 mutants; selective enhancement of receptor binding in the granular retrosplenial cortex of NRG1 mutants and reduction of 5- receptor binding in the substantia nigra of WT	—
NRG1	Subchronic Δ-9 THC during adolescence	[133]	Altered expression of proteins involved in vesicular release of neurotransmitters, 5-HT neurotransmission, and growth factor expression	Reduced hippocampal expression of heat shock proteins and oxidative stress	Altered expression of proteins implicated in NMDA-mediated glutamatergic neurotransmission	—
NRG1	Social defeat during adolescence	[86]	Increased novelty-induced activity; decreased social novelty preference; PPI disruption; decreased anxiety	—	Selective decrease in anxiety and working memory in stressed NRG1 mutants; protective effect of NRG1 genotype on disruption of sucrose preference following social defeat	—
NRG1	Chronic restraint stress during adolescence	[153]	—	Increased NMDA receptor binding in ventral part of the lateral septum and dentate gyrus	PPI disruption in NRG1 only following chronic stress exposure; altered patterns of NMDA receptor binding in infralimbic subregion of medial prefrontal cortex and dentate gyrus; decreased corticosterone levels, as well as increased apical dendritic spine density and decreased apical dendritic lengths and complexity in layer II/III pyramidal neurons of the medial prefrontal cortex	—
DISC1	Prenatal Poly I:C	[50]	Enlargement of the lateral ventricles	Increased anxiety in open field; decreased volume of amygdala and left/right periaqueductal grey; decrease in linear density of spines in pyramidal neurons of the CA1 region	Increase in anxiety in elevated plus maze and increased immobility in forced swim test in DISC1 mutants; decreased social interaction in challenged DISC1 offspring; decreased linear spine density on dendrites of granule cells of the dentate gyrus in DISC1 mutants only; opposite effects on lateral ventricle volume (increased in WT, decreased in mutants)	—
DISC1	Prenatal Poly I:C	[104]	Decreased PPI in DISC1 Q31L mutant; decreased LI and social affiliative behaviour in DISC1 L100P line	Decreased PPI and LI; disruption of spatial discrimination and object exploration	More prominent PPI and LI deficits in L100P mutants; impaired working memory and sociability in challenged DISC1 offspring; increase of Poly I:C-induced increase in IL-6 in brains of DISC1 mutants	Coadministration of IL-6 antagonist with Poly I:C reversed Poly I:C-related deficits in mutants and controls
DISC1	Neonatal Poly I:C	[105, 106]	—	—	Selective deficits in short-term memory and object recognition memory in DISC1 mutants; increased behavioural sensitivity to MK-801 in DISC1 mice exposed to Poly I:C; selective decrease in parvalbumin-positive interneurons in the medial prefrontal cortex	Cognitive deficits in Poly I:C-treated DISC1 mutants improved by clozapine while haloperidol had no effect; clozapine suppressed the augmentation of MK-801-induced hyperactivity
DISC1	Prenatal lead exposure	[107]	Enlargement of lateral ventricles; decreased anxiety in open field	Increased anxiety in open field; increased anxiety in elevated plus maze; increased MX-801 responsivity; decreased PPI; enlargement of lateral ventricles	Heightened responsivity to the NMDAR antagonist MK-801 and increased PPI disruption in female DISC1 mice; synergistic decrease in exploratory activity and synergistic increase in lateral ventricular volume in DISC1 mutants	Systemic administration of D-serine, a coagonist at the NMDA receptor, reversed PPI deficits in female lead-exposed mutants
DISC1	Subchronic Δ-9 THC during adolescence	[137]	Decrease in contextual fear memory; decreased synaptic CB1R expression in the prefrontal cortex, hippocampus, and amygdala	Decrease in synaptic CB1R expression in the prefrontal cortex, hippocampus, and amygdala	Disruption in cue-dependent fear memory	—
DISC1	Social defeat during adulthood	[154]	Decreased PPI in DISC1 L100P; impaired LI in L100P and DISC1 Q31L; decreased sociability and social novelty in Q31L mutants	Increased immobility in forced swim test; decreased sucrose intake in the sucrose consumption test	Decrease in exploratory activity and sociability and social novelty in L100P; increase in anxiety in the elevated plus maze in L100P but not Q31L mutants exposed to social defeat	—
DISC1	Prolonged social isolation during adolescence	[51, 155]	—	—	PPI disruption, forced swim immobility, and methamphetamine-induced locomotion, in isolated DISC1 mutants; decreased tyrosine hydroxylase expression, total tissue DA levels, and DA in the frontal cortex; increased DA release in the nucleus accumbens; altered DNA methylation of tyrosine hydroxylase, BDNF, and FK506 binding protein 5 genes	RU-486 normalized basal and methamphetamine-induced extracellular DA, tyrosine hydroxylase, and DA D2 receptor levels in G × E model; RU-486 also reversed PPI, forced swim test deficits, and changes in amphetamine-induced activity in this model
COMT	Subchronic Δ-9 THC during adolescence	[123]	Improved spatial working memory in COMT KO males	Decreased object recognition, social novelty preference, and anxiety	Increased hyperactivity and greater disruption of working memory in THC-treated COMT KO mice	—
COMT	Subchronic Win 55,212 [CB1R agonist] during adolescence	[143]	—	Decreased social novelty preference; decreased anxiety in the light-dark test	Selective disruption of PPI in cannabinoid-treated COMT mutants; decreased sensitivity to disruptive effects on sociability in mutants relative to WT	—
COMT	Subchronic Δ-9 THC during adolescence	[144]	Increased CB1R intensity in the prefrontal cortex; decreased CB1R intensity in the hippocampus; parvalbumin cell size decreased in COMT heterozygotes	Decreased cell density in the VTA	Decreased parvalbumin cell intensity in the prefrontal cortex; decreased DA cell size in VTA; increased CB1R intensity in hippocampus of THC-treated COMT mutants	—

BDNF, brain-derived neurotrophic factor; CB1R, cannabinoid receptor 1; COMT, catechol-O-methyltransferase; DA, dopamine; Δ-9 THC, delta-9-tetrahydrocannabinol; DISC1, disrupted in schizophrenia 1; , gamma-aminobutyric acid type A receptor; IL-6, interleukin 6; KO, knockout; LI, latent inhibition; NMDA receptor, N-methyl-D-aspartate receptor; NRG1, neuregulin-1; PPI, prepulse inhibition; 5-, serotonin receptor; VTA, ventral tegmental area.