Suppression of inhibitory G protein signaling in forebrain pyramidal neurons triggers plasticity of glutamatergic neurotransmission in the nucleus accumbens core
Introduction
Durable molecular and cellular adaptations evoked by repeated exposure to drugs of abuse such as cocaine complicate the development of treatment strategies for addiction (Koob and Volkow, 2010, Luscher, 2013). These adaptations are thought to underlie the observation, for example, that exposure to stress or re-exposure to drug can reinstate cocaine-seeking behavior in humans and animal models, even after a prolonged period of abstinence (Shaham et al., 2003).
The nucleus accumbens (NAc) is a node within the mesocorticolimbic circuitry that is implicated in goal-directed behavior, and that mediates the rewarding and reinforcing effects of cocaine and other drugs of abuse (Hyman et al., 2006, Kalivas and Volkow, 2005, Koob and Volkow, 2010). Adaptations in cortical and limbic glutamatergic inputs to NAc medium spiny neurons (MSNs), which account for 90–95% of the neurons in this brain region, have been implicated in a number of behaviors linked to cocaine addiction including locomotor sensitization, craving, and relapse (Conrad et al., 2008, Kalivas, 2009, Lobo and Nestler, 2011, Luscher, 2013, Shaham and Hope, 2005, Wolf, 2016).
Cocaine-induced plasticity of glutamatergic transmission in the NAc impacts signaling via AMPA glutamate receptors (AMPAR) (Bowers et al., 2010, Pierce and Wolf, 2013, Wolf, 2016). Repeated in vivo exposure to cocaine increases dendritic spine number on NAc MSNs (Churchill et al., 1999, Li et al., 1997, Robinson and Kolb, 2004), and the cell surface levels of AMPAR in the NAc (Boudreau and Wolf, 2005), while also enhancing behavioral responses to subsequent infusion of AMPA into the NAc (Cornish and Kalivas, 2000, Pierce et al., 1996, Suto et al., 2004). Indeed, AMPA administered to either the NAc core or shell evoked enhanced locomotor activity in rats previously given repeated cocaine injections, as compared to saline-treated controls (Pierce et al., 1996). Interestingly, the potentiation of AMPAR-dependent signaling in NAc MSNs has been shown to emerge during extended periods of withdrawal following repeated cocaine administration, and subsequent exposure to stress or cocaine can depotentiate AMPAR-dependent signaling in these neurons (Jedynak et al., 2016, Kourrich et al., 2007).
Previously, we reported adaptations in AMPAR-dependent signaling in NAc core and shell MSNs from mice lacking G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels (Arora et al., 2010), prevalent postsynaptic mediators of metabotropic inhibitory signaling in the central nervous system (Lujan et al., 2014, Luscher and Slesinger, 2010). Constitutive ablation of the integral neuronal GIRK channel subunit, GIRK2, correlated with increased density of excitatory synapses and increased synaptic expression of AMPAR in both the NAc core and shell, along with increased amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) in NAc MSNs. More recently, we reported that repeated non-contingent cocaine administration evoked a persistent suppression of GIRK-dependent signaling in layer 5/6 pyramidal neurons of the prelimbic cortex (PrLC) (Hearing et al., 2013), a key glutamatergic projection to the NAc core (Krettek and Price, 1977, Sesack et al., 1989), suggesting that reduced GIRK-dependent inhibitory signaling in glutamatergic inputs to the NAc may underlie some of the cellular and behavioral effects associated with repeated cocaine administration. In support of this contention, viral RNAi-mediated suppression of GIRK-dependent signaling in layer 5/6 of the mouse PrLC yielded a “pre-sensitized” state characterized by an enhanced acute motor-stimulatory effect of cocaine (Hearing et al., 2013).
Collectively, these findings raise the intriguing possibility that decreased GIRK channel activity in afferent glutamatergic inputs to the NAc may contribute to the plasticity of AMPAR-mediated neurotransmission in the NAc seen following repeated cocaine administration. We tested key elements of this premise using a transgenic Cre-dependent recombination approach and novel conditional GIRK knockout mouse lines. We found that the persistent genetic suppression of GIRK-dependent signaling in forebrain pyramidal neurons enhanced AMPAR-dependent neurotransmission in D1R-expressing MSNs in the NAc core, in a manner comparable to that seen following repeated cocaine administration in wild-type mice, and yielded enhanced motor stimulatory responses to cocaine.
Section snippets
Animals
All animal studies were approved by the Institutional Animal Care and Use Committee at the University of Minnesota. The generation and characterization of Girk2fl/fl mice was described previously (Kotecki et al., 2015). B6.Cg-Tg(Drd1a-tdTomato)6Calak/J (D1R-tdTomato) and Tg(Camk2a-cre)T29-1Stl/J (CaMKIICre) lines were purchased from The Jackson Laboratory (Bar Harbor, ME), and the Tg(Drd2-EGFP)S118Gsat (D2R-EGFP) strain was obtained from the Mutant Mouse Regional Resource Center. Mice were
Generation of conditional Girk1-/- mice
GIRK channels in mouse layer 5/6 PrLC pyramidal neurons are formed by GIRK1 and GIRK2; genetic ablation of either subunit correlates with decreased GIRK-dependent inhibitory signaling and increased excitability in these neurons (Hearing et al., 2013). Recently, we described the development of a conditional Girk2 knockout mouse (Victoria et al., 2016). To permit cell-specific ablation of GIRK1, we generated a conditional Girk1 mutant (Girk1fl/fl) by flanking a short internal coding sequence exon
Discussion
Repeated non-contingent cocaine administration triggers a persistent reduction in GIRK-dependent signaling in layer 5/6 PrLC pyramidal neurons, including neurons that project to the NAc core (Hearing et al., 2013). This adaptation is evident within a day of cocaine withdrawal and persists for weeks. In contrast, enhanced AMPAR-dependent neurotransmission in NAc core MSNs emerges after an extended period of withdrawal from repeated cocaine exposure (Jedynak et al., 2016). In this study, we asked
Statement of interest
None.
Acknowledgements
The authors would like to thank Alex Shnaydruk for assistance with maintaining the mouse colony. This work was supported by NIH grants to KW (MH061933 and DA034696).
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