Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, USA.
Department of Neuroscience, University of Texas Southwestern Medical School, Dallas, TX, USA.
Mol Psychiatry. 2014 May;19(5):573-9. doi: 10.1038/mp.2013.49. Epub 2013 Apr 30.
Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage-gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs.
神经元放电是大脑功能的基本要素；而电压门控钾 (K(+)) 通道通过动作电位的复极化来调节放电。Kv3 型通道（Kv3.1-Kv3.4）代表一类电压门控 K(+) 通道，具有快速放电特性。Kv3.1 通道亚基主要定位于皮质小清蛋白 (PV)-阳性、抑制性中间神经元。这些中间神经元的放电特性参与建立皮质神经元群体的正常伽马振荡和同步，被认为是人类大脑更高信息处理的特征。精神分裂症（SZ）与皮质伽马同步和信息处理异常有关，特别是与工作记忆和执行功能障碍有关。在这里，我们报告了正常人类大脑中 Kv3.1b 和 Kv3.2 蛋白的分布，结果表明 Kv3.1b 仅限于新皮质区域，而 Kv3.2 在新皮质和皮质下区域大量表达。在 SZ 病例中，Kv3.1b 蛋白水平在新皮质中降低，但仅在未接受抗精神病药物（APD）治疗的病例中；在接受抗精神病药物治疗的病例中，Kv3.1 水平正常。Kv3.2 在分布或水平上在正常和 SZ 病例之间没有差异，也不受任何测试区域的 APD 影响。在接受慢性 APD 治疗的实验室啮齿动物中，证实了 SZ 新皮质中 APD 增加 Kv3.1b 蛋白水平的现象。这些发现表明 SZ 新皮质中的 Kv3.1b 通道蛋白减少，而 APD 可恢复这种缺陷。这种改变可能与 SZ 的皮质表现和对 APD 的治疗反应密切相关。
