Prenatal Cannabis Exposure Disrupts Hippocampal Signaling by Modulating Glutamate Receptor Function

Abstract

Learning and memory depend on proper hippocampal function and are mediated largely through glutamatergic neurotransmission. The ionotropic glutamate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) and N-methyl-D-aspartate (NMDA) receptors (NMDARs), play critical roles in synaptic plasticity, long-term potentiation, and memory formation. Cannabis and its primary psychoactive constituent, Δ9-tetrahydrocannabinol (THC), are known to influence glutamatergic neurotransmission and impair learning and memory. Although developmental cannabinoid exposure has been associated with long-lasting cognitive deficits, relatively few studies have examined the effects of prenatal oral THC exposure, despite oral cannabis products becoming increasingly common. Furthermore, the receptor-level mechanisms underlying these deficits remain poorly understood. The overall goal of this dissertation was to determine how prenatal oral THC exposure alters hippocampal glutamatergic neurotransmission and to identify mechanisms capable of restoring receptor dysfunction. Using a rat model of prenatal THC exposure, we examined the expression and single-channel activity of AMPARs and NMDARs in hippocampal synaptosomes. Prenatal exposure to THC reduced the probability of opening of AMPARs and altered channel kinetics while disrupting the cooperative channel activity without significantly changing receptor expression. In contrast, prenatal THC exposure reduced GluN2A expression, altered ERK signaling, and increased NMDAR channel activity. These findings demonstrate that developmental THC exposure produces persistent alterations in glutamate receptor function that are not always accompanied by changes in receptor abundance. Because polysialic acid (PSA), an extracellular glycan molecule, is an important regulator of neuronal plasticity and glutamatergic signaling, its role in cannabinoid-induced receptor dysfunction was also investigated. Prenatal THC exposure reduced hippocampal PSA expression, while exogenous PSA restored both AMPAR and NMDAR activity toward control levels. Collectively, these findings demonstrate that prenatal oral THC exposure disrupts hippocampal glutamatergic neurotransmission at the receptor level and identify PSA-mediated signaling as a potential mechanism for restoring synaptic function following developmental cannabinoid exposure.