Abstract
Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content.