Altered neurotransmission in the mesolimbic reward system of Girk^−/− mice

Abstract

J. Neurochem. (2010) 114, 1487–1497. Abstract Mice lacking the Girk2 subunit of G protein‐gated inwardly rectifying K+ (Girk) channels exhibit dopamine‐dependent hyperactivity and elevated responses to drugs that stimulate dopamine neurotransmission. The dopamine‐dependent phenotypes seen in Girk2−/− mice could reflect increased intrinsic excitability of or diminished inhibitory feedback to midbrain dopamine neurons, or secondary adaptations triggered by Girk2 ablation. We addressed these possibilities by evaluating Girk−/− mice in behavioral, electrophysiological, and cell biological assays centered on the mesolimbic dopamine system. Despite differences in the contribution of Girk1 and Girk2 subunits to Girk signaling in midbrain dopamine neurons, Girk1−/− and Girk2−/− mice exhibited comparable baseline hyperactivities and enhanced responses to cocaine. Girk ablation also correlated with altered afferent input to dopamine neurons in the ventral tegmental area. Dopamine neurons from Girk1−/− and Girk2−/− mice exhibited elevated glutamatergic neurotransmission, paralleled by increased synaptic levels of α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate glutamate receptors. In addition, synapse density, α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor levels, and glutamatergic neurotransmission were elevated in medium spiny neurons of the nucleus accumbens from Girk1−/− and Girk2−/− mice. We conclude that dopamine‐dependent phenotypes in Girk2−/− mice are not solely attributable to a loss of Girk signaling in dopamine neurons, and likely involve secondary adaptations facilitating glutamatergic signaling in the mesolimbic reward system.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

“…Cocaine-Induced Locomotor Activity GIRK2 DA KO mice, similar to constitutive Girk2 -/-mice (Arora et al, 2010), are more sensitive to the locomotorstimulatory effect of cocaine. This unconditioned behavioral response to cocaine is DA dependent and tempered by GABA B R-and autoreceptor-mediated inhibitory feedback to VTA DA neurons.…”

“…The amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) were elevated in MSNs of the nucleus accumbens (NAc) shell from constitutive Girk2 -/-mice, observations paralleling an increase in AMPA receptor levels at excitatory synapses in these neurons (Arora et al, 2010). To discern whether this adaptation is driven by loss of GIRK-dependent signaling in VTA DA neurons, we compared mEPSCs in NAc core and shell MSNs from GIRK2 DA WT and GIRK2 DA KO mice.…”

“…Interestingly, Girk2 ablation yields a complete loss of VTA DA neuron GIRK channel activity (Beckstead et al, 2004;Cruz et al, 2004), whereas Girk3 ablation yields increased sensitivity of the residual channel (GIRK2 homomer) to receptor activation (Labouebe et al, 2007;Lunn et al, 2007). The opposing contributions of GIRK2 and GIRK3 are also sensed at the behavioral level, where loss of GIRK2 in DA neurons correlates with increased locomotor effects of cocaine and morphine, while constitutive Girk3 ablation correlates with decreased locomotor-stimulatory effect of morphine (Arora et al, 2010;Kotecki et al, 2015). The GIRK channel in VTA DA neurons undergoes activity-dependent bidirectional modulation; burst firing increases GIRK-dependent signaling in VTA DA neurons, whereas tonic firing suppresses channel activity (Lalive et al, 2014).…”

“…Constitutive Girk2 -/-mice are hyperactive, a phenotype normalized by D 1 DA receptor (D 1 R) blockade (Blednov et al, 2002). Moreover, Girk2 -/-mice exhibit enhanced locomotor activation in response to morphine and cocaine (Arora et al, 2010;Kotecki et al, 2015). The many phenotypes and adaptations associated with global Girk2 ablation, however, confound interpretation of these data (Lujan et al, 2014).…”

“…The many phenotypes and adaptations associated with global Girk2 ablation, however, confound interpretation of these data (Lujan et al, 2014). For example, VTA DA neurons, NAc medium spiny neurons (MSNs), and layer 5/6 medial prefrontal cortex (mPFC) pyramidal neurons from Girk2 -/-mice exhibit elevated AMPA receptor-mediated neurotransmission (Arora et al, 2010;Hearing et al, 2013). The recent availability of mice lacking GIRK2 in DA neurons permits a more precise evaluation of the role of GIRK-dependent signaling in modulating DA neuron excitability and cocaine-induced behaviors (Kotecki et al, 2015).…”