Chronic Alcohol Exposure Alters Behavioral and Synaptic Plasticity of the Rodent Prefrontal Cortex

Abstract

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP) showed that CIE exposure was associated with altered expression of long-term potentiation (LTP). Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC.

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…With regard to synaptic plasticity, in the present study, CIE treatment induced a sustained increase in glutamatergic signaling following a spike-timing dependent LTP protocol that was similar to that reported for deep-layer neurons in the prelimbic sub-division of the mPFC (Kroener et al, 2012). Although the cellular mechanisms underlying these changes are not completely understood, they likely arise from a combination of changes in factors that control intrinsic excitability and excitatory synaptic signaling.…”

“…These findings add to a growing understanding of ethanol-induced changes in glutamate receptor function and expression in the frontal cortex and confirm that such changes are both region and WD time dependent. For example, two previous studies from our group that used the same CIE protocol reported either no significant change in NMDA receptor expression in lOFC at 0 or 7 days post WD , or an increase in GluN1 and GluN2B expression in the mPFC at the 0 but not 7 day WD time point (Kroener et al, 2012). A similar increase in GluN2B expression in the mPFC was reported for CIE-exposed rats killed 3 h after the last ethanol vapor treatment (Kim et al, 2014), while no change in GluN1 or GluN2(A/B) was noted 1 week post WD (TranthamDavidson et al, 2014), despite an increase in NMDAmediated EPSCs.…”

“…Although not examined in the present study, our previous report showed that CIE exposure increased spine density in lOFC neurons due to an increase in highly plastic long thin spines . Changes in spine density and/or subtype have also been reported in mPFC neurons from CIE-treated mice (Kroener et al, 2012) and rats (Kim et al, 2014), whereas an increase in apical dendrite length of prelimbic mPFC neurons has been observed in CIE-exposed mice (Holmes et al, 2012).…”

“…Long-term potentiation (LTP) of glutamatergic synaptic transmission was examined using a spike-timing-dependent plasticity (STDP) protocol as described previously (Kroener et al, 2012). With a potassium gluconate internal solution, EPSPs were evoked at 0.1 Hz at − 70 mV until a stable baseline was obtained for 10 min.…”

“…However, these measures provide only a static measure of synaptic efficacy and do not indicate whether the affected neurons show altered sensitivity to plasticity-inducing inputs. To determine whether CIE exposure produces dynamic changes in glutamatergic plasticity, we used a STDP protocol previously shown to produce a short-term potentiation of AMPAmediated EPSPs in the mPFC (Kroener et al, 2012). In these studies, single EPSPs were induced by focal electrical stimulation applied close to the recorded neuron.…”