Impact of Cannabinoid Across the Lifespan (ICAL)

ICAL SYNAPTIC PROJECT (PROJECT 2): SUMMARY Disturbances in memory associated with cannabis use during adolescence (1-4) strongly suggest that the drug has age- and sex-specific effects on synaptic plasticity and associated cognitive functions. There is, however, little information on the neurobiological bases underlying such effects. Our Project has shown that adolescent THC exposure (‘ado-THC’) causes pronounced, sexually dimorphic, and enduring impairments to synaptic plasticity underlying learning. Specifically, we found ado-THC leads to marked deficits in long-term potentiation (LTP) in the lateral perforant path (LPP) projections to the dentate gyrus (LPP-LTP) in rodents of both sexes. It also causes enduring deficits in LTP in the CA3 projection to CA1 (CA1-LTP) but for females only. Importantly, these effects are accompanied by disturbances in a fundamental aspect of episodic memory known to depend on the LPP. Motivated by evidence that microglial functions are impaired by ado-THC (Project 1) we tested if these cells normally influence LTP in hippocampus and found that pharmacological elimination of microglia mimicked the effects of ado-THC on LPP plasticity and episodic memory but did not impair CA1-LTP. These findings led to a ‘microglia hypothesis’ for the origin of LPP-LTP and memory problems resulting from ado-THC. The proposed research will test this hypothesis and evaluate the basis of sex differences in CA1 in three specific aims. Aim 1 will test predictions of the microglia hypothesis for impairments in LPP plasticity by determining (a) if microglial depletion mimics effects of ado-THC on synaptic signaling, (b) if newly devised conditional knockout (cKO) mice engineered to prevent the microglial responses to ado-THC protect LPP-LTP from impairment and (c) if microglial replacement in adulthood can restore full LPP function after ado-THC. Aim 2 will address the question of why ado-THC impairs CA1-LTP in females only. It is known that female, but not male, rodents require local estrogen acting at synaptic estrogen receptors to induce stable CA1-LTP. Preliminary results indicate that ado- THC blocks estrogen effects on synaptic strength and spine F-actin content in CA1. Aim 2 will test the hypothesis that ado-THC disrupts estrogen responsivity at excitatory synapses and specifically impairs estrogen effects on the actin cytoskeleton that stabilize female CA1-LTP. Finally, Aim 3 will determine the breadth of ado-THC effects on episodic memory and if these changes are (a) sexually dimorphic and (b) depend on microglial dysfunction. Together, the studies will identify synaptic mechanisms through which ado- THC exerts sexually dimorphic effects on episodic memory and, thus, higher cognitive function.