Abstract
Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases such as schizophrenia. GABAergic hypofunction in the prefrontal cortex (PFC) is a cardinal pathological feature of schizophrenia and may be a mechanism by which the PFC loses its ability to regulate sub-cortical dopamine (DA) resulting in schizophrenia-like neuropsychopathology. In the present study, we exposed adolescent rats to Δ-9-tetra-hydrocannabinol (THC), the psychoactive component in marijuana. At adulthood, we characterized the functionality of PFC GABAergic neurotransmission and its regulation of sub-cortical DA function using molecular, behavioral and in-vivo electrophysiological analyses. Our findings revealed a persistent attenuation of PFC GABAergic function combined with a hyperactive neuronal state in PFC neurons and associated disruptions in cortical gamma oscillatory activity. These PFC abnormalities were accompanied by hyperactive DAergic neuronal activity in the ventral tegmental area (VTA) and behavioral and cognitive abnormalities similar to those observed in psychiatric disorders. Remarkably, these neuronal and behavioral effects were reversed by pharmacological activation of GABAA receptors in the PFC. Together, these results identify a mechanistic link between dysregulated frontal cortical GABAergic inhibition and sub-cortical DAergic dysregulation, characteristic of well-established neuropsychiatric endophenotypes.
Highlights
Adolescence is a highly vulnerable period for brain development, during which the prefrontal cortex (PFC) undergoes massive functional remodeling
Given our previous findings of significantly reduced GABAergic PFC glutamic acid decarboxylase-67 (GAD67) activity and PFC neuronal hyperactivity in following adolescent THC exposure, we hypothesized that pharmacologically restoring PFC GABAA receptor tone may reverse the hyperactive ventral tegmental area (VTA) DA neuron phenotype induced by adolescent THC exposure
We demonstrate that adolescent THC exposure induces persistent prefrontal GABA hypofunction in adulthood characterized by reduced expression levels of the GABAergic marker GAD67, increased spontaneous PFC pyramidal neuron bursting and firing rates and potentiated high gamma power oscillatory activity
Summary
Adolescence is a highly vulnerable period for brain development, during which the PFC undergoes massive functional remodeling. Regulation of sub-cortical emotional processing centers, and maturation of normal adult behavior and cognition[8, 9] Due to their strategic location on local PFC GABAergic circuits, cannabinoid type 1 receptors (CB1R) play a key role in prefrontal maturational processes, maintaining the balance of excitatory/inhibitory neuronal activity and associated cortical oscillatory states[10,11,12]. We report that adolescent THC exposure induces a long-term loss of GABAergic inhibition within the PFC that persists into adulthood This phenotype was characterized by dysregulated γ oscillatory activity, downregulation of GABAergic protein markers, increased medial PFC (mPFC) output neuron activity, hyperactive sub-cortical DAergic activity and a range of cognitive and affective abnormalities resembling to those observed in psychiatric diseases such as schizophrenia. Pharmacological activation of GABAA receptors directly in the mPFC, which shares functional-anatomical properties with the human dorsolateral PFC38, 39, reversed these deficits, demonstrating that aberrant PFC-mesolimbic connectivity following adolescent THC exposure is a critical neuropathological mechanism underlying an increased risk for later adulthood schizophrenia-like abnormalities
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