Prefrontal Cortical Circuits and Working Memory in Mutant Models of Schizophrenia

Otherwise diverse genetic influences on risk for schizophrenia may converge on a common set of molecular and cellular processes in prefrontal cortex, mediating impairments in cognition and vulnerability for the disorder when combined with other factors. Using mutant mouse models that carry mutations within genes linked or associated with schizophrenia, we have begun to discover these mechanisms. In recent work, we have used behavioral, imaging and electrophysiological approaches to examine prefrontal cortex function in a mouse model carrying a null mutation of the dtnbp1 gene which encodes the protein dysbindin. Mice carrying the null mutation exhibit impairments in spatial working memory, as well as other behavioral alterations often associated with prefrontal dysfunction, including impaired social motivation. These impairments depend upon specific adaptations in aspects of pre- and post-synaptic glutamatergic function, including compromised high frequency release of the transmitter and lower than normal post-synaptic NMDA receptor function. The latter effect is transcriptional and directly linked to the cognitive deficits. In this sense, the mechanisms mediating dysbindin's influence on the prefrontal cortex overlaps with the dominant neural circuit model for schizophrenia which proposes NMDA hypofunction as crucial to the expression of disorder symptoms. By further exploring the role for these mechanisms across candidate genes, new insights into the "final molecular pathways" to schizophrenia risk may be identified.