Development of Cortical Gaba Circuitry: Identifying Periods of Vulnerability to Schizophrenia
Year: 2013
Type: article
Abstract: The development of cognitive functioning is disrupted in many individuals who will later be diagnosed with schizophrenia, lagging behind healthy comparison subjects by 1-2 standard deviations at clinical onset. Cognitive dysfunction often appears years before clinical onset, is the best predictor of functional outcome, and is increasingly recognized as a central feature of schizophrenia. The domains of cognitive functioning affected in schizophrenia are mediated, at least in part, by prefrontal cortex (PFC) GABA neurons, which show molecular alterations in postmortem studies in schizophrenia. One common environmental risk factor for schizophrenia is chronic cannabis use, which disrupts cognitive function most prominently during adolescence, a time of flux in PFC circuitry that may be a sensitive period for the effects of cannabis use on neural circuit maturation. Parvalbumin (PV)-containing GABA neurons may be particularly vulnerable to risk factors for schizophrenia since they are altered in the disease, important for neural activity associated with cognitive functioning, and have a lengthy period of postnatal maturation. However, the nature of PV neuron subtype-specific developmental changes is not clear. Therefore, this dissertation focuses on understanding the timing of altered expression profiles of GABA-related mRNA levels in schizophrenia, the impact of chronic cannabis exposure during adolescence on GABA circuits of the monkey PFC, and the cell type-specific nature of postnatal maturation of influential GABAergic connections. Indeed, we find that the profile of GABA transmission markers in postmortem PFC tissue in schizophrenia can be explained by disrupted development of their mRNA levels; that chronic exposure to the psychoactive compound in cannabis during adolescence alters the GABAergic mRNA levels in monkey PFC; and that two populations of PV neurons have distinctive modes of maturation in monkey PFC.
Author: Gil D. Hoftman
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W13645684