GAD67 Deficiency in Parvalbumin Interneurons Produces Deficits in Inhibitory Transmission and Network Disinhibition in Mouse Prefrontal Cortex
GAD67 Deficiency in Parvalbumin Interneurons Produces Deficits in Inhibitory Transmission and Network Disinhibition in Mouse Prefrontal Cortex
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DOI：
10.1093/cercor/bht322
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发表时间：
2015-05-01
期刊：
影响因子：
3.7
通讯作者：
Huang, Z. Josh
中科院分区：
文献类型：
--
作者：
Lazarus, Matthew S.;Krishnan, Keerthi;Huang, Z. Josh
在哺乳动物的新皮质中，神经回路的微妙平衡受到由不同类别的GABA能中间神经元介导的丰富的抑制控制机制的调节。GABA能神经元共有的一个关键步骤是合成GABA，由谷氨酸脱羧酶(GAD)的两种异构体催化。其中，GAD67是限速酶。GAD67水平受神经活动的调节，在多种神经精神障碍中会发生变化。然而，GAD67水平改变对抑制传递的意义仍不清楚。GAD65的存在，突触后GABA受体的调节，以及皮质中间神经元的多样性，使得GAD67水平与GABA传递之间的联系并不直接。在这里，我们选择性地移除了幼年小鼠PV中间神经元中GAD67基因的一个等位基因Gad1。我们发现PV向前额叶皮质锥体神经元的传递存在明显的缺陷，同时PV细胞的兴奋性和兴奋/抑制平衡增加。成年小鼠的突触缺陷恢复，表明参与了动态平衡和代偿机制。这些结果表明，GAD67水平直接影响突触抑制。因此，PV细胞中GAD67的缺乏可能导致疾病状态下的皮质功能障碍；突触缺陷的可逆性表明抑制电路的非永久性损害。
In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.