Abstract
The striatum is a key structure for movement control, but the mechanisms that dictate the output of distinct subpopulations of medium spiny projection neurons (MSNs), striatonigral projecting and dopamine D1 receptor- (D1+) or striatopallidal projecting and dopamine D2 receptor- (D2+) expressing neurons, remains poorly understood. GABA-mediated tonic inhibition largely controls neuronal excitability and action potential firing rates, and we previously suggested with pharmacological analysis that the GABAA receptor β3 subunit plays a large role in the basal tonic current seen in D2+ MSNs from young mice (Ade et al., 2008; Janssen et al., 2009). In this study, we demonstrated the essential role of the β3 GABAA receptor subunit in mediating MSN tonic currents using conditional β3 subunit knock-out (β3f/fDrd2) mice. Cre-lox genetics were used to generate mice where Cre recombinase was expressed under the D2 receptor (Drd2) promoter. We show that while the wild-type MSN tonic current pattern demonstrates a high degree of variability, tonic current patterns from β3f/fDrd2 mice are narrow, suggesting that the β3 subunit is essential to striatal MSN GABA-mediated tonic current. Our data also suggest that a distinct population of synaptic receptors upregulate due to β3 subunit removal. Further, deletion of this subunit significantly decreases the D2+ MSN excitability. These results offer insight for target mechanisms in Parkinson’s disease, where symptoms arise due to the imbalance in striatal D1+ and D2+ MSN excitability and output.
Highlights
Medium spiny neurons (MSNs) are GABAergic projection neurons of the striatum, and project either to the substantia nigra pars reticulata though a direct pathway or the globus pallidus through an indirect pathway (Gerfen et al, 1990)
The striatum is a key structure for movement control, but the mechanisms that dictate the output of distinct subpopulations of medium spiny projection neurons (MSNs), striatonigral projecting and dopamine D1 receptor- (D1+) or striatopallidal projecting and dopamine D2 receptor- (D2+) expressing neurons, remains poorly understood
GENERATION OF THE CONDITIONAL β3 GABAA RECEPTOR SUBUNIT KNOCK-OUT IN D2+ MSNs To study the role of the β3 GABAA receptor subunit in striatal MSN tonic current, the subunit was rendered non-functional by deleting exon 3 (Ferguson et al, 2007)
Summary
Medium spiny neurons (MSNs) are GABAergic projection neurons of the striatum, and project either to the substantia nigra pars reticulata though a direct pathway or the globus pallidus through an indirect pathway (Gerfen et al, 1990). MSNs of the direct pathway express the dopamine D1 receptors (D1+); their activity is thought to facilitate movement. Dopamine D2 receptors (D2+) are expressed on indirect pathway MSNs that inhibit movement initiation. MSN excitability and synchrony is thought to be altered in dopamine-depleted animal models of Parkinson’s disease (Costa et al, 2006; Fino et al, 2007; Azdad et al, 2009; Burkhardt et al, 2009; Jáidar et al, 2010). Optogenetic activation of striatal D2+ MSNs in vivo mimicked Parkinson’s disease with decreased movement initiation and increased freezing behavior (Kravitz et al, 2010). The intrinsic mechanisms that control MSN output are of crucial interest in understanding the underlying factors that mediate altered neuronal excitability
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