Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α.
Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α.
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DOI：
10.1038/mp.2017.124
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发表时间：
2017-08
影响因子：
11
通讯作者：
Rajadhyaksha AM
中科院分区：
文献类型：
--
作者：
Kabir ZD;Che A;Fischer DK;Rice RC;Rizzo BK;Byrne M;Glass MJ;De Marco Garcia NV;Rajadhyaksha AM
CACNA 1C编码L型钙离子通道的Cav1.2亚基，已成为几种神经精神疾病的最突出和高度可复制的易感基因之一。Cav1.2通道在参与脑发育和神经元功能的钙介导过程中起着至关重要的作用。在CACNA 1C基因内，疾病相关的单核苷酸多态性与社交和认知处理受损以及前额叶皮质（PFC）结构和活动改变有关。这些研究结果表明，异常Cav1.2信号可能有助于通过受损的PFC功能神经精神病相关的疾病症状。在这里，我们表明，小鼠窝藏cacna 1c的前脑兴奋性多巴胺能神经元（fbKO），我们以前曾报道表现出焦虑样行为的损失，表现出社会行为缺陷和受损的学习和记忆。此外，局灶性敲除cacna 1c在成人PFC重演的社会赤字和焦虑样行为的升高，但不是在学习和记忆的赤字。在PFC的cacna 1c fbKO小鼠的电生理和分子研究显示，较高的E/I比在第5层锥体神经元和较低的一般蛋白质合成。这与mTORC 1及其下游mRNA翻译起始因子eIF 4 B和4 EBP 1的活性降低以及mRNA翻译抑制剂eIF 2 α磷酸化水平升高同时发生。值得注意的是，ISRIB（一种抑制磷酸化eIF 2 α对mRNA翻译影响的小分子抑制剂）的全身治疗足以逆转成年cacna 1c fbKO小鼠的社会缺陷和焦虑样行为升高。ISRIB还使PFC中较低的蛋白质合成和较高的E/I比率正常化。因此，本研究确定了神经精神病相关内表型中的新Cav1.2机制和潜在的未来治疗靶点。
CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.
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影响因子：
3.8
作者：
Bicks LK;Koike H;Akbarian S;Morishita H
通讯作者：
Morishita H
影响因子：
11
作者：
Gershon, E. S.;Grennan, K.;Busnello, J.;Badner, J. A.;Ovsiew, F.;Memon, S.;Alliey-Rodriguez, N.;Cooper, J.;Romanos, B.;Liu, C.
通讯作者：
Liu, C.
DOI：
10.1073/pnas.1112667108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Bader, Patrick L.;Faizi, Mehrdad;Shamloo, Mehrdad
通讯作者：
Shamloo, Mehrdad
影响因子：
64.8
作者：
Costa-Mattioli, M;Gobert, D;Sonenberg, N
通讯作者：
Sonenberg, N
影响因子：
30.8
作者：
Ferreira, Manuel A. R.;O'Donovan, Michael C.;Meng, Yan A.;Jones, Ian R.;Ruderfer, Douglas M.;Jones, Lisa;Fan, Jinbo;Kirov, George;Perlis, Roy H.;Green, Elaine K.;Smoller, Jordan W.;Grozeva, Detelina;Stone, Jennifer;Nikolov, Ivan;Chambert, Kimberly;Hamshere, Marian L.;Nimgaonkar, Vishwajit L.;Moskvina, Valentina;Thase, Michael E.;Caesar, Sian;Sachs, Gary S.;Franklin, Jennifer;Gordon-Smith, Katherine;Ardlie, Kristin G.;Gabriel, Stacey B.;Fraser, Christine;Blumenstiel, Brendan;Defelice, Matthew;Breen, Gerome;Gill, Michael;Morris, Derek W.;Elkin, Amanda;Muir, Walter J.;McGhee, Kevin A.;Williamson, Richard;MacIntyre, Donald J.;MacLean, Alan W.;Clair, David St;Robinson, Michelle;Van Beck, Margaret;Pereira, Ana C. P.;Kandaswamy, Radhika;McQuillin, Andrew;Collier, David A.;Bass, Nicholas J.;Young, Allan H.;Lawrence, Jacob;Ferrier, I. Nicol;Anjorin, Adebayo;Farmer, Anne;Curtis, David;Scolnick, Edward M.;McGuffin, Peter;Daly, Mark J.;Corvin, Aiden P.;Holmans, Peter A.;Blackwood, Douglas H.;Gurling, Hugh M.;Owen, Michael J.;Purcell, Shaun M.;Sklar, Pamela;Craddock, Nick
通讯作者：
Craddock, Nick