Spike timing-dependent plasticity is a well-characterized cellular model of NMDARdependent synaptic plasticity that describes changes in synaptic efficacy in response to repeated pairings of near Gomisin-D coincident preand postsynaptic APs. For the induction of STDP, we used a pattern of high-frequency postsynaptic activation that facilitates induction of Ca2+ spikes and NMDAR activation in basal dendrites that leads to LTP of the amplitude of the EPSP. Using this protocol, we observed STDP in mPFC slices from all three treatment groups. However, in CIE exposed mice, induction of NMDAR-dependent STDP was significantly 
increased compared to that observed in control slices at 50�C60 min post-pairing. Consistent with the CIE-induced increase in NMDAR-dependent STDP, it was recently reported that Chloroquine Phosphate chronic ethanol exposure transforms NMDAR dependent long-term depression into LTP in the nucleus accumbens shell and also reduced the threshold required for LTP induction in the hippocampus. Although the exact molecular mechanisms that underlie altered synaptic plasticity that we observed are unclear, they likely involve enhanced Ca2+ influx through NR2B-containing receptors. Interestingly, NMDAR on pyramidal neurons of the PFC have distinct biophysical properties compared with those in sensory cortical areas due to a significantly higher NR2B subunit expression in the PFC. Thus, the subunit composition of these NMDAR conveys unique properties to PFC networks that support flexible control of behavior, but it may also make the PFC especially vulnerable to the effects of prolonged ethanol. Under conditions that do not favor induction of synaptic plasticity AMPA receptors did not appear to be altered by CIE. However, our data clearly do not exclude a role for AMPARs during the induction of NMDARdependent synaptic plasticity. As demonstrated in many brain regions, postsynaptic LTP typically requires NMDAR activation and Ca2+ influx, which results in the rapid recruitment of AMPA receptors as well as a concomitant modification in the phosphorylation state of synaptic AMPA receptors. Longer forms of LTP also require the synthesis of new proteins to sustain a long-term memory. Our physiology experiment only examined short changes in synaptic plasticity and thus the role of CIE-induced alterations in NMDAR function for long-term synaptic changes is as of yet unclear. However, in addition to an increase in the synaptic targeting of NMDARs, we also found that CIE induced morphological changes in a subpopulation of spines on the basal dendrites of deep-layer pyramidal neurons in the mPFC, consistent with the idea of long-term synaptic plasticity. Specifically, CIE exposure produced a persistent increase in the density of mature, mushroom spines without altering total spine density. This observation is also consistent with findings from a study in the nucleus accumbens that showed similar specific alterations in spine morphology in a model of chronic alcohol drinking and repeated deprivation. Changes in the structural plasticity of dendritic spines have also been observed in response to exposure to psychostimulants. Thus, our data provide further evidence of structural remodeling in response to alcohol and drug exposure. Although our observations in acute slices demonstrate that CIE exposure alters NMDAR function and NMDAR-dependent synaptic plasticity in the mPFC, it is not clear how these changes will affect neural networks in the mPFC. Based upon previous observations that enhanced expression of NR2B subunits promotes enhanced learning and memory, one might expect that chronic ethanol-induced increases in NR2B receptors.