Prefrontal Cortical Fast-Spiking Interneurons in Healthy Animals and in a Developmental Model of Schizophrenia

Abstract

Schizophrenia is a serious mental illness from which approximately 1% of the world's population suffers. Current treatments are effective against positive symptoms such as hallucinations and delusions, but do little to ameliorate the cognitive deficits which are a devastating component of the disease. A current hypothesis is that hypofunction of cortical fast spiking interneurons (FSI) is an important substrate of these deficits. However, the mechanisms producing this hypofunction are unclear. Based on the observation that NMDA receptor antagonists like ketamine are psychotomimetic and produce a disinhibited cortex, it has been suggested that hypofunctional NMDA receptors may underlie the hypothesized deficit in FSI function. Recently, this has been called into question based on the observation that NMDA receptors contribute minimally to synaptic responses in adult FSI. Here we tested whether adult FSI express functional NMDA receptors in the adult rat cortex. We found that while only a subset of FSI express NMDA receptors at synaptic locations, all FSI express functional NMDA receptors at some location. In light of this, the hypothesis that hypofunctional NMDA receptors on FSI contribute to cortical disinhibition and cognitive symptoms in schizophrenia should not be disregarded. As schizophrenia is a developmental disorder with late adolescent or early adult onset, it is important to understand possible links between early-life abnormalities and adult-onset symptoms. In a second set of experiments, we used the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia to test the possibility that developmental oxidative stress could provide a link between neonatal insults and cortical dysfunction in adulthood. Indeed, we found evidence that developmental oxidative stress causes electrophysiological deficits in the adult NVHL cortex. This implicates oxidative stress as a link between early-life insults and adult-onset psychiatric disorders. Furthermore, this indicates that developmental antioxidant treatment may be beneficial for individuals at high risk for developing schizophrenia.