Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD 21201.
eNeuro. 2017 Sep 21;4(5). doi: 10.1523/ENEURO.0162-17.2017. eCollection 2017 Sep-Oct.
GABA released from presynaptic sites induces short-lived phasic inhibition mediated by synaptic GABA receptors (GABARs) and longer-duration tonic inhibition mediated by extrasynaptic GABA or GABA receptors (GABARs). A number of studies have found that contactin-associated protein 2 (Cntnap2) knockout (KO) mice, a well-established mouse model of autism, exhibit reduced interneuron numbers and aberrant phasic inhibition. However, little is known about whether tonic inhibition is disrupted in Cntnap2 KO mice and when the disruption of inhibition begins to occur during postnatal development. We examined tonic and phasic inhibition in layer 2/3 pyramidal cells of primary visual cortex of Cntnap2 KO at two different developmental stages, three to four and six to eight weeks of age. We found that both phasic inhibition and GABAR but not GABAR-mediated tonic inhibition was reduced in pyramidal cells from six- to eight-week-old Cntnap2 KO mice, while in three- to four-week-old mice, no significant effects of genotype on tonic or phasic inhibition was observed. We further found that activation of tonic currents mediated by δ-subunit-containing GABARs reduced neural excitability, an effect that was attenuated by loss of Cntnap2. While the relative contribution of tonic versus phasic inhibition to autism-related symptoms remains unclear, our data suggest that reduced tonic inhibition may play an important role, and δ-subunit-containing GABARs may be a useful target for therapeutic intervention in autism.
从突触前部位释放的 GABA 会诱导短暂的突触 GABA 受体（GABARs）介导的相性抑制和由 extrasynaptic GABA 或 GABA 受体（GABARs）介导的长时程紧张性抑制。许多研究发现，接触蛋白相关蛋白 2（Cntnap2）敲除（KO）小鼠，一种公认的自闭症小鼠模型，表现出中间神经元数量减少和异常的相性抑制。然而，关于 Cntnap2 KO 小鼠中紧张性抑制是否被破坏以及抑制的破坏何时在出生后发育过程中开始发生，知之甚少。我们在三个至四个和六个至八个星期龄的两个不同发育阶段检查了 Cntnap2 KO 小鼠初级视觉皮层第 2/3 层锥体神经元中的紧张性和相性抑制。我们发现，来自 6 至 8 周龄 Cntnap2 KO 小鼠的锥体神经元中，相性抑制和 GABAR 但不是 GABAR 介导的紧张性抑制均降低，而在 3 至 4 周龄的小鼠中，基因型对紧张性或相性抑制没有显著影响。我们进一步发现，δ-亚基包含的 GABAR 介导的紧张性电流的激活降低了神经元兴奋性，而 Cntnap2 的缺失减弱了这种作用。虽然紧张性抑制相对于相性抑制对自闭症相关症状的相对贡献仍不清楚，但我们的数据表明，紧张性抑制的减少可能起重要作用，并且 δ-亚基包含的 GABAR 可能是自闭症治疗干预的一个有用靶点。
