40.2 DYSBINDIN-1 REGULATES DENDRITIC SPINE DEVELOPMENT DURING ADOLESCENCE

Abstract

Background: Schizophrenia is a debilitating mental illness with a lifetime prevalence of ∼0.4-0.5% worldwide. Schizophrenia patients have a variety of symptoms including positive symptoms, negative symptoms and cognitive impairment. Cognitive impairment is a core symptom of schizophrenia but cannot be effectively treated by current medications. The clinical symptoms of schizophrenia arise from the structural and functional abnormalities of the brain, such as fewer dendritic spines (subcellular structures accommodating synapses), defective synaptic transmission and alterations in γ oscillation (synchronized neural activity oscillating at ∼30-100 Hz, essential for cortical computation). DTNBP1 is a gene associated with the risk of schizophrenia. It encodes dysbindin-1 protein, which is abundantly expressed in glutamatergic neurons of both human and mouse hippocampi. Dysbindin-1 expression is decreased in the hippocampus and cortex of schizophrenia patients. Methods: We examined dendritic spines, synaptic transmission, and spatial working memory in dysbindin-1 null mutant (sandy) mice and mice treated with blockers of dopamine D2 receptors. Results: We found that the hippocampal neurons of sandy mice have fewer dendritic spines during adolescence but not in adulthood. This is caused by inhibition of spine maturation. In sandy mice, deficient dysbindin-1 expression causes over-expression of dopamine D2 receptors on the cell surface, which leads to GluN2B internalization and cAMP reduction, thereby reducing spine number. The transient decrease of dendritic spines during adolescence causes mis-wiring of neural connections and impairment of spatial working memory in adulthood. Blocking D2 receptors in sandy mice during adolescence, but not in adulthood, can prevent the impairment of synaptic connectivity and working memory. Conclusions: Our findings indicate D2 receptor over-activation during adolescence causes cognitive impairment and intervention during adolescence is critical to protect cognitive function from being damaged by D2 receptor dysfunction.