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 | — |
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| 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 | — |
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| 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 | — |
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| 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 | — |
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| NRG1 | Subchronic cannabidiol during adulthood | [136] | Increased novelty-induced activity; disrupted PPI; decreased 5-HT2a 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 GABAA receptor binding in the granular retrosplenial cortex of NRG1 mutants and reduction of 5-HT2a receptor binding in the substantia nigra of WT | — |
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| 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 | — |
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| 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 | — |
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| 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 | — |
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| 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) | — |
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| 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 |
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| 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 |
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| 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 |
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| 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 | — |
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| 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 | — |
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| 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 |
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| 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 | — |
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| 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 | — |
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| 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; GABAA, 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-HT2A, serotonin 2A receptor; VTA, ventral tegmental area.