Department of Pharmacology and Physiology, Georgetown University School of Medicine Washington, DC, USA.
Front Cell Neurosci. 2011 Jul 28;5:15. doi: 10.3389/fncel.2011.00015. eCollection 2011.
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 GABA(A) 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 GABA(A) receptor subunit in mediating MSN tonic currents using conditional β3 subunit knock-out (β3f/f(Drd2)) 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/f(Drd2) 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.
纹状体是运动控制的关键结构，但支配不同亚群的中间棘投射神经元（MSNs）的输出的机制仍然知之甚少，这些亚群包括纹状体苍白球投射和多巴胺 D1 受体（D1+）或纹状体黑质投射和多巴胺 D2 受体（D2+）表达神经元。GABA 介导的紧张性抑制在很大程度上控制神经元兴奋性和动作电位发放率，我们之前通过药理学分析表明，GABA(A) 受体 β3 亚基在年轻小鼠的 D2+ MSN 中观察到的基础紧张性电流中起着重要作用（Ade 等人，2008 年；Janssen 等人，2009 年）。在这项研究中，我们使用条件性 β3 亚基敲除（β3f/f(Drd2)）小鼠证明了 β3 GABA(A) 受体亚基在介导 MSN 紧张性电流中的重要作用。Cre-lox 遗传学用于生成 Cre 重组酶在 D2 受体（Drd2）启动子下表达的小鼠。我们表明，虽然野生型 MSN 紧张性电流模式表现出高度的可变性，但来自β3f/f(Drd2)小鼠的紧张性电流模式较窄，表明β3 亚基对于纹状体 MSN GABA 介导的紧张性电流是必需的。我们的数据还表明，由于β3 亚基的缺失，一个不同的突触受体群体上调。此外，该亚基的缺失显著降低了 D2+MSN 的兴奋性。这些结果为帕金森病的靶点机制提供了深入了解，在帕金森病中，由于纹状体 D1+和 D2+MSN 兴奋性和输出的不平衡，出现了症状。
