Monoaminergic regulation of prefrontal cortex inhibition during adolescence

The goal of this project is to determine the cellular mechanisms underlying the age-dependent modulation of cortical activity, focusing on interneuronal circuits in the prefrontal cortex. Such developmental regulation is highly relevant to the pathophysiology of schizophrenia since converging findings stress interneuron deficits during development as a potential basis for this disorder (www.nimh.nih.gov/.../ neurodevelopment workgroup report). The prefrontal cortex (PFC) is of particular interest due to its role in working memory and decision-making, two cognitive abilities impaired in schizophrenia. PFC impairment in schizophrenia is typically accompanied by reduced gamma (i.e., 30–50 Hz) oscillations in the EEG, an effect that is thought to be an expression of reduced cortical inhibitory transmission. What is missing is the link between the developmental regulation of cortical interneuronal function and PFC impairment. Our recently published work and preliminary studies indicate that PFC interneuronal activity is enhanced after puberty. This postpubertal/late adolescent facilitation is thought to be related to the delayed maturation of the mesocortical dopamine (DA) system and the enhanced facilitation of glutamatergic drive onto these GABAergic interneurons. If during development, such interneuronal activity does not become enhanced, PFC inhibitory control will be altered at maturity. Our preliminary studies indicate that multiple pre- and postsynaptic factors contribute to maintaining the age-dependent facilitation of prefrontal interneuron activity (Figure).

Based on this model, we predict that a dysregulation of any of these components (a, b, c, d) is sufficient to change the trajectory of the normal interneuronal facilitation observed during late adolescence. If interneuronal activity does not become enhanced during development, prefrontal inhibitory control will be altered at maturity. Such impairment would be important for the onset of prefrontal cognitive deficits as observed in schizophrenia and other psychiatric syndromes. Thus, elucidating the cellular mechanisms and synaptic events preceding and accompanying the periadolescent maturation of prefrontal interneuronal function is critical to our understanding of the role of cortical inhibitory control during development.

Neural Bases of Parkinson's Disease: non-dopaminergic neuronal adaptations within the cortico-basal ganglia system