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

Sven Kroener,Justin T Gass,L Judson Chandler,Howard C Becker,Patrick J Mulholland,Natasha N New,Olivier Jacques Manzoni

doi:10.1371/journal.pone.0037541

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.

Highlights

The prefrontal cortex (PFC) is involved in executive cognitive processes that include supervisory control over impulsive behaviors and the ability to flexibly shift attentional processes as the situation demands
Using a mouse model in which chronic alcohol dependence is induced by repeated cycles of exposure to alcohol vapors [26,27,28,29], we observed that chronic alcohol exposure lead to persistent increases in NMDA/AMPA current ratio at glutamatergic synapses of layer V pyramidal neurons in medial PFC (mPFC) slices
As a direct measure of synaptic plasticity, we examined spike-timing-dependent plasticity (STDP) in the acute slice preparation and found that chronic intermittent ethanol (CIE) exposure was associated with an aberrant form of enhanced NMDARmediated plasticity

Summary

Introduction

The prefrontal cortex (PFC) is involved in executive cognitive processes that include supervisory control over impulsive behaviors and the ability to flexibly shift attentional processes as the situation demands. Chronic alcohol exposure has been reported to increase the synaptic expression of NR2B subunit-containing NMDARs [7,8,9,10,11,12,13]. This increase presumably occurs as a homeostatic adaptive response to the prolonged reduction of NMDAR activity in the presence of alcohol. NMDARs containing the NR2B subunit have been especially implicated in synaptic plasticity and alterations in learning and memory [14,15]. Using a mouse model of alcohol dependence that involves repeated cycles of alcohol exposure, the goal of the present study was to determine whether the plasticity of medial PFC (mPFC) is altered in response to chronic alcohol exposure.

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Conclusion