Abstract
Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene–environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene–environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.
Highlights
Schizophrenia is a severe psychiatric disorder whose symptoms are generally classified into three major groups: positive symptoms, negative symptoms, and cognitive impairments
Since schizophrenia is implicated in aberrant monoamine neurotransmission especially in the cortical and striatal regions [34] and altered postmortem monoamine profiles have been observed in transgenic DISC1 model (tgDISC1) animal models [25, 35], we investigated the postmortem levels of monoamines in the brain regions that have been commonly associated with schizophrenia
A significant effect was absent for genotype, LPS treatment, or their interaction for females, suggesting that neither tgDISC1 nor LPS influenced baseline behavior (Figure 2A and B)
Summary
Schizophrenia is a severe psychiatric disorder whose symptoms are generally classified into three major groups: positive (psychotic) symptoms, negative symptoms, and cognitive impairments. Accumulating evidence implicates the disrupted-in-schizophrenia 1 protein (DISC1) as a strong candidate susceptibility factor for schizophrenia [2,3,4,5]. Studies about the biological function of DISC1 using yeast two-hybrid screening revealed DISC1 to be an intracellular scaffold protein, interacting with various proteins to regulate neurodevelopmental and synaptic processes [3,4,5]. DISC1 has been shown to be critically involved in synaptic pruning, and its malfunction could cause abnormal spine morphology [5]. Overpruning of cortical synapses during critical neurodevelopmental periods has been proposed to underlie schizophrenia, as many studies investigating postmortem brain samples of schizophrenic patients have reported reduction of spine density on cortical and hippocampal pyramidal neurons [7,8,9]
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