Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex

A truncated disrupted in schizophrenia 1 (Disc1) gene increases the risk of psychiatric disorders, probably affecting cortical interneurons. Here, we sought to determine whether this cell population is affected in mice carrying a truncated (Disc1) allele (DN-DISC1). We utilized whole cell recordings to assess electrophysiological properties and modulation by dopamine (DA) in two classes of interneurons: fast-spiking (FS) and low threshold-spiking (LTS) interneurons in wild-type and DN-DISC1 mice. In DN-DISC1 mice, FS interneurons, but not LTS interneurons, exhibited altered action potentials. Further, the perineuronal nets that surround FS interneurons exhibited abnormal morphology in DN-DISC1 mice, and the DA modulation of this cell type was altered in DN-DISC1 mice. We conclude that early-life manipulation of a gene associated with risk of psychiatric disease can result in dysfunction, but not loss, of specific GABAergic interneurons. The resulting alteration of excitatory-inhibitory balance is a critical element in DISC1 pathophysiology.