PGC-1α Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons
PGC-1α Provides a Transcriptional Framework for Synchronous Neurotransmitter Release from Parvalbumin-Positive Interneurons
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DOI：
10.1523/jneurosci.1222-14.2014
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发表时间：
2014-10-22
影响因子：
5.3
通讯作者：
Cowell, Rita M.
中科院分区：
文献类型：
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作者：
Lucas, Elizabeth K.;Dougherty, Sarah E.;Cowell, Rita M.
越来越多的证据强烈暗示转录辅激活因子过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）在多种神经系统疾病的病理生理学，但PGC-1 α在大脑中的下游基因靶点仍然是个谜。先前的数据表明，PGC-1 α主要集中在抑制性神经元中，并且PGC-1 α是整个皮质中神经元间特异性Ca 2+结合蛋白小清蛋白（PV）表达所需的。为了确定PGC-1 α在神经组织中的其他可能的转录靶点，我们对过表达PGC-1 α的神经母细胞瘤细胞进行了微阵列，挖掘了与中间神经元生理相关的基因的结果，并测量了PGC-1 α表达不足和过表达的小鼠中这些基因的皮质基因和蛋白质表达。我们观察到新的PGC-1 α依赖性转录物的双向调节，这些转录物跨越突触[突触结合蛋白2（Syt 2）和复合蛋白1（Cplx 1）]、结构[神经丝重链（Nefh）]和代谢[中性胆固醇酯水解酶1（Nceh 1）、腺苷酸激酶1（Ak 1）、肌醇多磷酸5-磷酸酶J（Inpp 5 j）、ATP合成酶线粒体F1复合物0亚基（Atp 5 o），植烷醇-CoA-2羟化酶（Phyh）和ATP合成酶线粒体F1复合体α亚基1（Atp 5a 1）]功能。神经元特异性基因Syt 2、Cplx 1和Nefh在发育过程中以与PGC-1 α一致的表达模式上调，并在皮质中间神经元中表达。PV阳性神经元中PGC-1 α的条件性缺失显著降低了这些基因的皮质转录表达，促进了GABA的异步释放，并损害了长期记忆。总的来说，这些数据表明PGC-1 α是正常PV阳性中间神经元功能所需的，并且该中间神经元亚群中PGC-1 α的缺失可能导致疾病状态下的皮质功能障碍。
Accumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1 alpha in the brain have remained enigmatic. Previous data demonstrate that PGC-1 alpha is primarily concentrated in inhibitory neurons and that PGC-1 alpha is required for the expression of the interneuron-specific Ca2+-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1 alpha in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1 alpha, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1 alpha. We observed bidirectional regulation of novel PGC-1 alpha-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (Cplx1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex 0 subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex alpha subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, Cplx1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1 alpha and were expressed in cortical interneurons. Conditional deletion of PGC-1 alpha in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1 alpha is required for normal PV-positive interneuron function and that loss of PGC-1 alpha in this interneuron subpopulation could contribute to cortical dysfunction in disease states.