Maturation of the prefrontal cortical GABAergic system during adolescence: Role of NMDA receptors

• Main Author: Thomases, Daniel R
• Format: Dissertation
• Language: English
• Subjects: neurosciences; pharmacology
• ISBN: 132171372X; 9781321713725

Functional disruptions of the prefrontal cortex (PFC) and its maturation are thought to contribute to the adolescent onset of cognitive deficits observed in many psychiatric disorders including schizophrenia. However, the neurobiology underlying these deficits remains unclear. Among the contributing factors is the functional maturation of PFC GABAergic activity during adolescence, a developmental process paralleled by an elevation of NMDAR-mediated glutamatergic drive to the PFC. To test if these events are mechanistically linked, we examined how transient blockade of NMDAR transmission (MK-801) during adolescence (postnatal day -P- 35 to 40) impacts PFC maturation and function. In vivo and in vitro electrophysiological recordings revealed an enduring deficit in PFC GABAergic transmission following adolescent MK-801 exposure. These deficits occurred without affecting PFC glutamatergic function, resulting in an imbalance of excitation and inhibition within the PFC (increased AMPA:GABA ratio). Notably, this state of PFC disinhibition resembles that seen in juvenile animals (P25-35), indicating a retention of a functionally immature PFC state into adulthood. Subsequent analysis of PFCdependent behaviors revealed deficits in both working memory and extinction of trace fear memory in adult rats that received MK-801 during adolescence. No deficits in PFC function were found when similar treatment was administered during adulthood (P75-80). Taken together, these results demonstrate that NMDA transmission during adolescence is necessary to enable the maturation of GABAergic function within the PFC.