CANNABINOID TYPE 1 RECEPTOR EXPRESSION, SYNAPTIC FUNCTION, AND PERTURBATION WITHIN THE DEVELOPING CEREBELLAR CORTEX
Barnes, Jesse Lee
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The endocannabinoid receptor 1 (CB1R) plays a neuromodulatory role throughout the central nervous system. A large proportion of CB1Rs are concentrated within the cerebellar cortex, a brain region known to control motor coordination and motor learning, but has been gaining recognition for cognitive involvement. A critical period of cerebellar development occurs during the third trimester of pregnancy in humans and the early postnatal period in rodents, a period involving neuronal proliferation, migration, and synaptogenesis. The endocannabinoid system has been implicated in playing a role in numerous neurodevelopmental processes. However, we lack a clear understanding of whether the endocannabinoid system is established during cerebellar growth, or whether cannabinoid receptor activation modulates trans-cellular signaling and other processes known to modulate neurodevelopment. Using a neurodevelopmental rodent model equivalent to third trimester human fetal tissue, we observed prominent and temporally unique immunohistochemical CB1R expression within all layers of the cerebellar cortex. Using patch-clamp electrophysiology, we characterized how CB1Rs modulate synaptic transmission. We observed CB1R actions at synapses onto granule cells, Golgi cells, and stellate/basket cells, but not Purkinje cells. This is contrary to mature Purkinje cell terminals, which exhibit a prominent reduction in vesicle release probability in response to cannabinoids. It is well established that granule cell migration rate is influenced by ambient glutamate, but it is currently unknown whether parallel fibers are the source of this glutamate, or whether CB1Rs can modulate glutamate levels. We therefore determined mossy fiber CB1R activation attenuates downstream parallel fiber glutamate release onto migrating granule cells, demonstrating that cannabinoids may mediate migration by controlling parallel fiber glutamate release. To explore this last point, we exposed rat pups to an exogenous cannabinoid and later subjected them to an accelerated rotarod task during adolescence. Cannabinoid-exposed rats showed deficiencies in learning the task, suggesting altered cerebellar development. The results of this dissertation provide evidence that CB1R expression within the developing cerebellar cortex uniquely modulates synaptic function during a critical period of cerebellar development, and exogenous CB1R activation may have developmentally exclusive behavioral implications. These implications may ultimately aid in shaping guidelines for cannabis use in pregnant women.