Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
Laboratory on Neurobiology of Compulsive Behaviors, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, United States.
Elife. 2020 Sep 1;9:e55729. doi: 10.7554/eLife.55729.
Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.
多巴胺能神经元的轴突支配纹状体，在那里它们有助于运动和强化学习。过去的研究表明，纹状体内的 GABA 紧张性抑制多巴胺的释放，但 GABA-A 受体是否直接调节传递或通过回路元件间接调节尚不清楚。在这里，我们使用全细胞和穿孔贴片记录来测试成年小鼠纹状体中主要多巴胺能神经元轴突和分支过程上的 GABA-A 受体。GABA 的应用使轴突去极化，但也降低了轴突尖峰的幅度，限制了传播并减少了纹状体多巴胺的释放。抑制的机制涉及钠离子通道失活和分流。最后，我们表明，正变构调节剂地西泮增强了多巴胺能轴突上的 GABA-A 电流，并直接抑制了释放，但也可能通过减少来自胆碱能中间神经元的兴奋而起作用。因此，我们揭示了 GABA-A 受体调节多巴胺释放的机制，并为苯二氮䓬类药物在纹状体中的作用提供了新的见解。
