Dominant-Negative Disrupted in Schizophrenia 1 Alters the Dopaminergic Modulation of Excitatory-Inhibitory Balance in the Prefrontal Cortex

Abstract

Dysfunction of inhibitory cells, especially of fast-spiking interneurons within the prefrontal cortex, is a convergent phenotype existing in patients with schizophrenia and within animal models of the disorder. Despite a large amount of research into the molecular and behavioral consequences of different manipulations, the electrophysiological phenotype of cells within relevant brain areas including the prefrontal cortex remains underexplored. In this dissertation, I utilized whole cell recordings to first differentiate between classes of neurons in the normal-developing prefrontal cortex and then discerned the pattern of their modulation by dopamine receptor D2 agonists. I then contrasted this normal, late-maturing phenotype with that in mice carrying a truncated human disrupted in schizophrenia 1 (DISC1) allele. I will show that fast-spiking interneurons in mice expressing mutated DISC1 lose their normal electrophysiological phenotype including a failure to attain a normal adult firing profile and dopamine response, and conclude that early-life gene disruption can result in electrophysiological dysfunction of GABAergic interneurons.