PROJECT SUMMARY The goal of this project is to explore the functional relevance of interactions between brain-derived neurotrophic factor (BDNF) and endogenous cannabinoids (eCB) in regulating activity-dependent synaptic plasticity in the neocortex and hippocampus. Although there is growing evidence for crosstalk between BDNF and eCBs, little is known regarding potential synaptic interactions. We have previously characterized the synaptic effects of eCBs and BDNF in layer 2/3 and layer 5 of somatosensory cortex as well as the CA1 area of hippocampus, and we have recently shown that the presynaptic effects of BDNF at cortical and hippocampal inhibitory synapses are mediated by the BDNF-induced release of eCBs from postsynaptic pyramidal cells. We have also found that BDNF causes release of eCBs at excitatory synapses, and this eCB signaling mitigates the direct facilitatory effects of BDNF at these synapses. We are now poised to explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. In particular, we will examine the interactions between endogenous BDNF-induced eCB release and activity-dependent eCB release in regulating the magnitude and direction of plasticity at excitatory and inhibitory synapses. These studies will combine electrophysiology and calcium imaging with pharmacological and genetic approaches to manipulate these signaling systems. We will also examine these signaling interactions using mice engineered to express common human single-nucleotide polymorphisms (SNPs) that affect either endogenous BDNF or anandamide levels. Importantly, we will carry out parallel studies using cultured human induced pluripotent stem cell (iPSC)-derived neurons generated from individuals who carry these same SNPs.