Endocannabinoid Signaling and Action Potential Backpropagation in the Neocortex

Discovered and named originally because of its responsiveness to marijuana (Cannabis sativa), or rather the primary psychoactive cannabinoid found in the Cannabis plant, the endogenous cannabinoid system in the mammalian brain is an archetypal retrograde neurotransmitter system. Consisting of endogenous ligands called endocannabinoids (eCBs) and their cognate type 1 cannabinoid (CB1) receptor, the endogenous cannabinoid system regulates synaptic transmission and plasticity throughout the brain. In layer 2/3 of the neocortex, eCB-mediated suppression of presynaptic GABA release results in enhanced excitability and increased action potential (AP) firing of postsynaptic pyramidal neurons (PNs). The eCB system is also involved in forms of spike timing-dependent synaptic plasticity that depend on backpropagating APs (bAPs) in cortical PNs. Dendritic backpropagation also plays an important role in many aspects of neuronal function, however little is known regarding modulation of backpropagation efficacy. Since bAPs are sensitive to GABA-mediated shunting inhibition, we therefore hypothesized hypothesis that the endogenous cannabinoid system may play a role in modulating AP backpropagation in dendrites. ^ The studies presented in this thesis explored a role for the endogenous cannabinoid system in modulating backpropagation in PN dendrites. Using a combination of dendritic calcium imaging and somatic patch clamp recordings from mouse somatosensory cortical slices, we found that activation of type 1 cannabinoid (CB1) receptors significantly potentiated bAP-induced calcium transients in apical dendrites of layer 2/3 PNs. This effect of cannabinoids was mediated by suppression of GABAergic transmission because it was prevented by a GABAA receptor antagonist and was significantly correlated with cannabinoid suppression of inhibitory synaptic activity. Furthermore, cannabinoids did not alter backpropagation in layer 5 PNs, consistent with the reduced expression of CB1 receptors at layer 5 inhibitory synapses. Finally, we found that induction of depolarization-induced suppression of inhibition (DSI) in layer 2/3 PNs caused a transient enhancement of bAP-induced dendritic calcium transients that was mediated by activity-dependent eCB release. Taken together, these results point to a potentially important role for the eCB system in regulating dendritic backpropagation and neuronal processes that depend on bAPs in layer 2/3 PNs.