Mouse models carrying Disc1 mutations may provide insights into how Disc1 genetic variations contribute to schizophrenia (SZ) susceptibility. Disc1 mutant mice show behavioral and cognitive disturbances reminiscent of SZ. To dissect the synaptic mechanisms underlying these phenotypes, we examined electrophysiological properties of cortical neurons from two mouse models, the first expressing a truncated mouse Disc1 (mDisc1) protein throughout the entire brain, and the second expressing a truncated human Disc1 (hDisc1) protein in forebrain regions. We obtained whole-cell patch clamp recordings to examine how altered expression of Disc1 protein changes excitatory and inhibitory synaptic transmissions onto cortical pyramidal neurons in the medial prefrontal cortex in 4-7 month-old mDisc1 and hDisc1 mice. In both mDisc1 and hDisc1 mice, the frequency of spontaneous EPSCs was greater than in wild-type littermate controls. Male mice from both lines were more affected by the Disc1 mutation than were females, exhibiting increases in the ratio of excitatory to inhibitory events. Changes in spontaneous IPSCs were only observed in the mDisc1 model and were sex-specific, with diminished cortical GABAergic neurotransmission, a well-documented characteristic of SZ, occurring only in male mDisc1 mice. In contrast, female mDisc1 mice showed an increase in the frequency of small-amplitude sIPSCs. These findings indicate that truncations of Disc1 alter glutamatergic and GABAergic neurotransmission both commonly and differently in the models and some of the effects are sex-specific, revealing how altered Disc1 expression may contribute to behavioral disruptions and cognitive deficits of SZ.
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