Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders

Abstract

Strong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-Schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.

Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness

“…Consistent with that evidence, many roles for DISC1 in neurodevelopment and synapse formation have been reported (17). Furthermore, mouse models that genetically modulate DISC1 by various methods demonstrate a decrease in parvalbumin immunoreactivity, consistent with the observations in human brains of patients as well as behavioral phenotypes relevant to psychiatric disease (20)(21)(22)(23).…”

Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner

“…The deficit in NMDA receptor levels did not prevent synapse formation in the developing brain of NR1-KD mice, but was sufficient to reduce spine density after adolescence, suggesting a greater necessity for intact NMDA receptor levels during synapse elimination or maintenance. Several recent studies illustrate how the cellular and behavioral consequences of developmental perturbations in neuron function may not become evident until adulthood (40)(41)(42)(43). Collectively, these studies and the present one demonstrate how genetic factors may act in an age-dependent fashion to produce adult-onset symptoms of CNS conditions associated with aberrant synaptic function.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Furthermore, the codependence of DISC1 and GABA in this period of development represents a point of convergence with other risk factors including NRG1 (Mata et al, 2010;Wood et al, 2009) and environmental exposures. Importantly, a dominant-negative DISC1 mutation had differential effects on the brain and behavior depending on the specific timing of its expression during development (Ayhan et al, 2011), which reinforces the importance of the timing of developmental insults.…”