Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure
Introduction
The nucleus accumbens (NAc) is a critical component of the brain reward system and is composed primarily of medium spiny neurons (MSNs) of which there are two distinct subtypes, D1 and D2 dopamine receptor expressing MSNs. A prominent and well described form of plasticity expressed in the NAc is NMDAR-dependent synaptic long-term depression (“NMDAR-LTD”). This form of plasticity requires the internalization of GluA2-containing AMPA receptors (Brebner et al., 2005, Jeanes et al., 2014) and several reports have shown that drugs of abuse and ethanol can disrupt the expression of NMDAR-LTD in the NAc (Abrahao et al., 2013, Jeanes et al., 2014, Jeanes et al., 2011, Kasanetz et al., 2010, Mao et al., 2009, Martin et al., 2006, Shen and Kalivas, 2012, Thomas et al., 2001). Indeed, Brebner et al. (2005) demonstrated that the disruption of the internalization of GluA2–containing AMPA receptors can alter the expression of behavioral sensitization to psychomotor stimulants. Therefore, such drug or ethanol-induced synaptic changes in the NAc may be critical neuroadaptive responses underlying the induction and/or expression of drug-induced behaviors (Luscher and Malenka, 2011).
Chronic intermittent ethanol (CIE) exposure is a well-established model for inducing ethanol dependence and increasing volitional ethanol intake (Becker and Lopez, 2004, Griffin et al., 2009a, Griffin et al., 2009b, Griffin, 2014, Lopez and Becker, 2005). In previous work from our lab, we focused upon identifying plasticity changes after a single cycle of CIE exposure in C57BL/6J mice. We observed a striking conversion in synaptic plasticity such that the NMDAR-LTD induction protocol which resulted in synaptic depression (LTD) in ethanol naïve mice produced synaptic potentiation (LTP) following a single cycle of ethanol vapor (Jeanes et al., 2011). At that time, we were unable to determine if ethanol differentially modulated plasticity between the D1 or D2 receptor-expressing MSN subtypes. In a second report, we used bacterial artificial chromosome (BAC) transgenic mice in which the expression of enhanced green fluorescent protein (eGFP) was controlled by the D1 receptor promoter in mice on a Swiss Webster background, thus allowing us to selectively record from D1+ or D1− MSNs (Matamales et al., 2009, Valjent et al., 2009). We observed that NMDAR-LTD was apparent only in D1+ MSNs with no change in synaptic strength in D1− MSNs following LFS conditioning. After CIE vapor exposure we found a reversal in the expression of plasticity in which LTD could be induced in D1− MSNs but not in D1+ MSNs (Jeanes et al., 2014). These findings strongly indicate that such differential neuroadaptations between MSN subtypes, which occur in response to CIE exposure, may underlie the development of excessive ethanol consumption.
However, this interpretation is limited by the fact that Swiss Webster mice do not voluntarily drink significant amounts of ethanol. Therefore, our first work using Drd1a-eGFP mice on the Swiss Webster background may not accurately reflect the neuroadaptations that contribute to the escalation of ethanol intake (Jeanes et al., 2014). In the present study, we used Drd1a-tdTomato mice on a C57BL/6 background, a strain that has a well-documented ethanol drinking phenotype. We aimed to characterize CIE induced effects on NMDAR function, synaptic plasticity, and intrinsic properties of MSNs in the NAc shell that occur in acute withdrawal, after a single 4 day cycle of intermittent ethanol exposure and thus may be critical for initiating neuroadaptive responses underlying enhanced ethanol intake in this widely adopted model.
Section snippets
Mice
Drd1a-tdTomato BAC transgenic male mice (MMRRC:030512-UNC) generated on a C57BL/6J background, at least 8 weeks of age, were used for in vivo ethanol vapor exposure and in vitro electrophysiological experiments. Mice were housed in pairs at 22 °C with a 12:12 light:dark cycle (lights on at 12 AM). Water and chow were available ad libitum. All of the following experimental procedures were approved by the University of Texas Institutional Animal Care and Use Committee.
Chronic intermittent ethanol exposure
Mice were exposed to ethanol
Differential modulation of plasticity in D1+ and D1− MSNs after CIE
In our previous work on Drd1a-eGFP on the Swiss Webster background we found that the expression of NMDAR-dependent LTD was restricted to D1+ MSNs in the NAc shell (Jeanes et al., 2014). In the present study using Drd1a-tdTomato mice on a C57BL/6J background we observed a similar pattern of expression in the air treated control mice where NMDAR-dependent LTD is expressed in D1+ MSNs (Fig. 1A, B) but not in D1− MSN (Fig. 1A, B). In CIE treated mice we observed a reversal in the expression of
Changes in intrinsic measures
In the present study we observed that CIE treatment can alter the excitability and intrinsic properties of MSNs in the NAc shell in a cell type specific manner. In ethanol naïve mice, D1− MSNs fired more action potentials in response to fixed current injections than D1+ MSNs (Fig. 2) suggesting that D1− MSNs are intrinsically more excitable. This result is similar to what has been previously reported in the dorsal striatum (Cepeda et al., 2008) as well as in the NAc core (Grueter et al., 2010).
Conclusions
The work in this study further supports the importance of understanding how NMDAR-dependent plasticity in the NAc can be altered by chronic drug or alcohol exposure. Although there may be unique neuroadaptations that are encoded with chronic drug or alcohol exposure there seems to be an interaction with the mechanisms of induction and/or expression of NMDAR-dependent plasticity in the NAc. Altered plasticity in the NAc may provide valuable information in detecting more specific changes in
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