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 V PFC neurons from juvenile rats, bath application of the CB1 agonist WIN55212-1 significantly decreased stimulus-evoked EPSCs and this effect was blocked by the CB1 antagonist SR141716A (Auclair et al., 2000). The decrease in excitatory transmission was mediated by a reduction in presynaptic release as WIN reduced the frequency but not the amplitude of evoked asynchronous EPSCs. WIN also shifted the plasticity of layer V PFC neurons toward long-term depression, consistent with its effect on presynaptic glutamate release. Endogenous cannabinoids also mediate PFC neuronal plasticity as stimulation of layer II/III afferents induces a long-lasting LTD in layer V pyramidal neurons from mouse PFC (Lafourcade et al., 2007). This depression was prevented by AM251, a CB1 antagonist, and was again mediated by a reduction in the frequency but not the amplitude of spontaneous EPSCs. The mechanism underlying the induction of EC synthesis was also investigated and was found to require mGluR5 receptors and activation of intracellular phospholipase C. Taken together, the
