Microglia-mediated adverse effect of cannabis on prefrontal cortex maturation and cognitive function

Adolescent heavy cannabis use increases the risk of impaired cognitive and executive functions. Clinical evidence indicates an adverse effect of chronic cannabis use on impulsivity, which is critically regulated by inhibitory control in executive function. The adverse effects of cannabis are mainly attributed to delta-9- tetrahydrocannabinol (THC), which primarily targets cannabinoid receptor type 1 (CNR1). The potency of THC in cannabis has increased in recent decades, posing a growing concern in society. Importantly, recent studies indicate CNR1 expression not only in neurons and astrocytes but also in microglia actively participating in adolescent maturation of the prefrontal cortex (PFC). Nevertheless, whether and how microglia mediate THC- induced aberrant adolescent PFC maturation, leading to impaired cognitive and executive functions remains poorly understood. This proposal aims to address these knowledge gaps by leveraging our recent work. We have reported that adolescent THC exposure induces amoeboid-like reactive morphological changes in microglia, specifically in the medial PFC (mPFC), which are exacerbated in a mouse model with a genetic risk factor for neuropsychiatric disorders. These effects are mediated by microglial CNR1, reducing the excitability of a particular type of excitatory neurons in mPFC called pyramidal-tract (PT) neurons. However, it is not yet known how adolescent THC exposure affects microglia function at the molecular level, what intercellular mechanisms direct the effects of THC on microglia-mPFC neuron interaction in a neuron subtype-specific manner, and whether hypoexcitability of PT neurons contributes to deficits in long-term cognitive and executive functions induced by adolescent THC exposure. Previous studies suggest that up-regulation of the cyclooxygenase-1 (COX-1)-prostaglandin E2 (PGE2) pathway in microglia is involved in reduced neuronal excitability. The mPFC PT neurons mediate response inhibition, an essential element of inhibitory control. Our preliminary data reveal that adolescent THC exposure induces up-regulation of the COX-1-PGE2 pathway in mPFC microglia, reactive morphological changes of mPFC microglia, reduced neuronal excitability of PT neurons, increased impulsivity, and deficits in response inhibition. Based on these findings, we hypothesize that adolescent THC exposure up-regulates the COX-1-PGE2 pathway in microglia via CNR1-mediated mechanisms, and that PGE2 secreted from microglia acts on neuronal PGE2 receptors and alters PT neuron maturation, thereby reducing their neuronal excitability. These mechanisms may be adolescence- and neuron subtype-specific, leading to deficits in response inhibition. To address these hypotheses, we will identify the time course of CNR1-mediated molecular and morphological changes in microglia induced by adolescent THC exposure. We will also identify the microglia-mediated mechanisms underlying adolescent THC-induced aberrant mPFC neuronal maturation. Finally, we will identify the specific neuronal circuits of mPFC PT neurons contributing to increased impulsivity and deficits in response inhibition induced by adolescent THC exposure.