Endocannabinoids (ECs) are neuromodulators derived from membrane phospholipids during periods of neuronal activity. Synthesis occurs in the postsynaptic neuron and is calcium dependent while EC action takes place on the presynaptic terminal, thus linking neuronal activity to the production of a retrograde messenger. ECs suppress the presynaptic release of GABA and glutamate through a process termed depolarization-induced suppression of inhibition or excitation (DSI, DSE) that requires activation of cannabinoid-type I receptors (CB1). ECs are rapidly degraded by enzymatic pathways involving fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) that preferentially inactivate anandamide and 2-acylglycerol (2-AG), the two best characterized endocannabinoids in the brain. EC modulation of synaptic transmission has been studied in most brain regions examined, including the cerebral cortex where both DSE and DSI have been described. However, most of these studies are confined to somatosensory cortex and show that in this region, EC modulation of signaling is layer specific with DSE and DSI occurring in layer II/III neurons while only DSE is observed in layer V pyramidal neurons (Fortin and Levine, 2007). In one study of layer
