LTP and LTD forms of synaptic plasticity are evident in the neocortex [37–41]. As demonstrated in various in vitro studies, both NMDAR dependent and independent mechanisms contribute to LTD in the neocortex. For example, the NMDAR-mediated LTD is dependent on activation of calcineurin, and the resulting internalization of AMPA type glutamate receptors [42]. One form of NMDAR independent LTD occurs via activation of metabotropic glutamate receptors [43, 44]. A second form of NMDAR independent LTD occurs via activation of cannabinoid type 1 (CB1) receptors, which causes a long-lasting decrease in release probability [45, 46]. Additionally, HFS-induced LTD in the PFC requires GABAA receptor functioning and can be inhibited by dopamine receptor antagonists [47]. With respect to the mechanisms underlying LTP in the neocortex, most studies reveal a role for NMDARs [48]. Notably, NMDAR-mediated LTP occurs in concert with activity of several protein kinases, including, CaMKII, PKC and PKA, which alter AMPA-type glutamate receptor phosphorylation, and insertion of GluR1-containing AMPA receptors into synapses [48]. Learning and memory functions dependent on the neocortex are impaired in subjects with moderate to severe AUDs,
