Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom.
J Neurosci. 2013 Sep 11;33(37):14850-68. doi: 10.1523/JNEUROSCI.1174-13.2013.
Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic α1β2γ2 GABA(A) receptors (GABA(A)Rs). Importantly, TC neurons also express extrasynaptic α4β2δ GABA(A)Rs, although how they cooperate with synaptic GABA(A)Rs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABA(A)R-lacking, α4 "knock-out" (α4(0/0)) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α4(0/0) pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABA(A)Rs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in α4(0/0) pairs, implying that the α4-GABA(A)R-mediated tonic conductance of relay neurons is dynamically influenced, in an activity-dependent manner, by nRT tonic firing intensity. Collectively, our data reveal that extrasynaptic GABA(A)Rs of the somatosensory thalamus do not merely provide static tonic inhibition but can also be dynamically engaged to couple presynaptic activity to postsynaptic excitability. Moreover, these processes are highly sensitive to the δ-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders.
丘脑皮质电路调节认知、感觉运动和与睡眠相关的网络过程，并在失神性癫痫发作期间产生病理性活动。丘脑网状核 (nRT) 神经元释放的 GABA 对丘脑皮质 (TC) 中继神经元的抑制性控制部分介导，主要通过突触 α1β2γ2 GABA(A) 受体 (GABA(A)R) 起作用。重要的是，TC 神经元还表达 extrasynaptic α4β2δ GABA(A)R，尽管它们如何与突触 GABA(A)R 合作以影响中继细胞抑制，特别是在生理相关的 nRT 输出期间，尚不清楚。为了解决这个问题，我们在源自野生型和 extrasynaptic GABA(A)R 缺失、α4"敲除" (α4(0/0)) 小鼠的脑切片中进行了突触偶联的 nRT 和 VB 复合体 TC 神经元的配对全细胞记录。我们证明，响应 nRT 爆发式放电产生的 VB 相抑制的持续时间在 α4(0/0) 对中大大缩短，表明动作电位依赖性相抑制通过 extrasynaptic GABA(A)R 的募集而延长。此外，nRT 紧张性放电频率对 VB 保持电流的影响在 α4(0/0) 对中也大大降低，这意味着 relay 神经元的 α4-GABA(A)R 介导的紧张性电导以活动依赖的方式，受 nRT 紧张性放电强度的动态影响。总的来说，我们的数据表明，感觉丘脑的 extrasynaptic GABA(A)R 不仅提供静态紧张性抑制，而且还可以动态参与将突触前活动与突触后兴奋性耦联。此外，这些过程对 δ 选择性变构调节剂 DS2 和 GABA 转运系统的操纵非常敏感，为丘脑皮质网络障碍的治疗干预提供了新的机会。
