Differential modulation of neocortical activity by endogenous cannabinoids

Cannabinoids are the chief bioactive ingredients in marijuana and hashish that affect the brain by acting at specific, membrane bound G-protein-coupled cannabinoid type-1 receptors (CB1Rs). In addition to exogenously consumed cannabinoids the CB1R can also be activated in response to endogenously produced cannabinoids (endocannabinoids). At the cellular level, endocannabinoids act as retrograde messengers that transiently inhibit the release of traditional neurotransmitters in several brain regions where the CB1R is expressed. In the neocortex, CB1R is differentially expressed across neocortical laminae, with highest levels of expression in layers 2/3 and 5. Although, exogenous cannabinoids have been shown to reduce inhibitory and excitatory postsynaptic currents in layers 2/3 and 5 respectively, little is known about the mobilization of endocannabinoids and how they may shape the activity of cortical pyramidal neurons, the main output cells of the cerebral cortex. In the present dissertation I demonstrate that both layer 2/3 and layer 5 pyramidal neurons are capable of activity-induced endocannabinoid mobilization which is dependent upon the magnitude and duration of activity-induced changes in intracellular calcium. In addition, I show that endocannabinoid signaling is differentially targeted to inhibitory and excitatory presynaptic terminals within layers 2/3 and 5 respectively. Therefore, endocannabinoid-mediated plasticity in the neocortex is highly specialized and may have important consequences with respect to the flow of sensory information across cortical lamina. Finally, understanding the regulation of neocortical activity by endocannabinoids will have important ramifications with respect to understanding cortical function and dysfunction.