The goal of the present study was to determine whether chronic alcohol exposure altered the plasticity of the mPFC. Using a mouse model in which chronic alcohol dependence is induced by repeated cycles of exposure to alcohol vapors, we observed that chronic alcohol exposure lead to persistent increases in NMDA/AMPA current ratio at glutamatergic synapses of layer V pyramidal neurons in mPFC slices. This increase was due to a selective enhancement of NMDA currents that persisted for at least 1 week of withdrawal. We also observed an increase in expression of NR1 and NR2B Pimozide subunits of the NMDA receptor in the insoluble PSD fraction, but this increase was more transient and was no longer observed after 1 week of withdrawal. In contrast to changes in NMDA receptors and currents, CIE exposure did not alter AMPA currents or expression of AMPA GluR1 subunits. CIE exposure also did not alter preFolinic acid calcium salt pentahydrate synaptic glutamate release as there was no change in mEPSC frequency. We also used diolistic labeling procedures to examine dendritic spines and found that while chronic ethanol did not alter the overall density of spines on basal dendrites of deep-layer pyramidal neurons, there was a significant increase in the number of mature spines that was still present 1 week after withdrawal from the last vapor inhalation exposure. As a direct measure of synaptic plasticity, we examined STDP in the acute slice preparation and found that CIE exposure was associated with an aberrant form of enhanced NMDARmediated plasticity. Finally, we used a PFC-dependent task that assesses different components of executive function and found that while CIE exposure did not alter acquisition or recall of a previously learned strategy, it did attenuate the ability of mice to adjust their strategy in response to changing task rules. Taken together, these results indicate that CIE exposure alters structural, functional and behavioral plasticity of the mPFC. Previous patchclamp slice electrophysiology studies have shown that acute ethanol inhibits NMDA currents in the mPFC and reduces NMDA-dependent Up-states that underlie persistent activity in this brain region. Following chronic exposure, NMDARs adapt to the inhibitory effects of alcohol by increasing their excitatory activity via enhanced expression at the synapse. In the present study, we observed similar changes in the mPFC of adult mice. Thus, the redistribution of NMDARs to the synapse may sensitize the synapse to subsequent synaptic plasticity events. However, an unexpected observation in the present study was the apparent mismatch in the persistence of CIEinduced increase in synaptic expression of NMDA receptors compared to synaptic NMDA currents. Using Western blotting procedures, we observed a transient elevation of synaptic NR1 and NR2B subunits that returned to baseline levels after 1-week of withdrawal, while electrophysiological measurement of synaptic NMDA currents showed they remained increased after 1-week of withdrawal. The reason for this discrepancy is not clear, but may relate to methodological considerations. For example, while electrophysiological recordings were restricted to layer V pyramidal neurons in the prelimbic subregion of the mPFC, Western blotting was carried out using tissue punches that included not only all layers of the prelimbic cortex, but also portions of the subregions surrounding the prelimbic PFC. Layer-specific effects on synaptic transmission have been observed for several drugs of abuse including alcohol. Furthermore, function with a return to baseline density so as to allow for subsequent plasticity events.