Disrupted in Schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism.To date, most of the research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life.DISC 1 has also been reported to regulate cAMP signaling by increasing PDE4 catabolism of cAMP when cAMP concentrations are high.In this study, we used patch-clamp recordings in prefrontal cortical slices to test the hypothesis that DISC1 regulates ionic currents and cellular activity in mature prefrontal cortical pyramidal neurons through its ability to regulate cAMP.DISC 1 function was reduced through shRNA viral knockdown in vivo or dialysis of recorded neurons with antibodies directed at DISC1 to provide immunoblockade in vitro.Reducing DISC1 function by either method resulted in an increase in SK channel-mediated hyperpolarization and a decrease in a TRPC channel-mediated sustained depolarization.Consistent with a role for DISC1 in regulation of cAMP signaling, stimulation of cAMP production with forskolin application had effects similar to reducing DISC1 by increasing SK-mediated hyperpolarization and decreasing TRPC-mediated depolarization.Lastly, inhibiting cAMP generation pharmacologically with guanfacine, an α2A-noradrenergie agonist, normalized both the hyperpolarization and depolarization in neurons dialyzed with DISC1 antibodies.Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal pattems of PFC activity through the loss of cAMP regulation of mGluR-mediated SK and TRPC channel activity.