Neural Plasticity

Review Article

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

Table 2

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
Gene target	Environmental exposure	Reference(s)	Genetic manipulation	Environmental manipulation	Gene × environment	Use of preventative or rescue strategy

Nurr1	Prenatal Poly I:C	[110]	Increased novelty-induced activity; decreased PPI, reduction in tyrosine hydroxylase-positive cells in the substantia nigra	Increased novelty-induced activity; decreased PPI; spatial working memory deficits; increase in tyrosine hydroxylase-positive cells in the VTA	Additive effects on novelty-induced hyperactivity; synergistic reduction in attentional shifting and sustained attention; decrease in DA D2 receptor immunoreactivity in the nucleus accumbens	—

Snap-25	Variable prenatal stress	[183]	Decreased PPI in the blind-drunk point mutant	PPI disruption	Decreased social novelty preference	Clozapine and haloperidol (to a lesser extent) reversal of PPI deficits was most pronounced in G × E group

Snap-25	Prenatal nicotine exposure	[184]	Increased novelty-induced activity and decreased social interaction	—	More pronounced novelty-induced hyperactivity and greater disruption of social interaction; deficits in DA D2 receptor-dependent induction of long-term synaptic depression	—

BDNF	Chronic methamphetamine exposure	[188]	—	Locomotor sensitisation and increased entropy	Decreased locomotor sensitisation and entropy in BDNF heterozygotes	—

BDNF	Chronic methamphetamine exposure	[189]	Decreased PPI and increased acoustic startle reactivity in BDNF heterozygotes	Locomotor sensitisation; increased sensitivity to MK-801 and amphetamine-induced PPI disruption	Increased sensitivity to amphetamine-induced PPI disruption in preexposed BDNF heterozygotes	—

RELN	Maternal separation	[193]	Decreased frequency of ultrasonic vocalisations; decreased activity in a novel environment	—	Decreased sensitivity to disruptive effects of maternal separation in heterozygous RELN mutants	—

RELN	Prenatal exposure to the pesticide chlorpyrifos Maternal separation	[192]	Decreased frequency of ultrasonic vocalisations	—	Prenatal chlorpyrifos: selective increase in ultrasonic vocalisation in RELN mutants; disrupted behavioural response to acute scopolamine Maternal separation: decreased social motivation in WT but not RELN mutants	—

RELN	Prenatal hypoxia	[194]	Increase in frontal cortex volume in RELN mutants	Reduction in glucocorticoid receptor protein levels in frontal cortex	Increase in frontal cortex volume in WT but opposite effect observed in RELN mutants; selective reduction in glucocorticoid receptor protein levels in hippocampus of RELN mutants; selective changes in brain expression of hypoxia-related proteins in mutants	—

BDNF, brain-derived neurotrophic factor; DA, dopamine; Δ-9 THC, delta-9-tetrahydrocannabinol; NURR1, nuclear receptor related 1 protein; PPI, prepulse inhibition; RELN, reelin; SNAP-25, synaptosome associated protein 25 kDa; VTA, ventral tegmental area; WT, wildtype.