Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity.
Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity.
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DOI：
10.1016/j.biopsych.2021.07.014
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发表时间：
2021-12-01
影响因子：
10.6
通讯作者：
Morón JA
中科院分区：
文献类型：
--
作者：
Frye HE;Izumi Y;Harris AN;Williams SB;Trousdale CR;Sun MY;Sauerbeck AD;Kummer TT;Mennerick S;Zorumski CF;Nelson EC;Dougherty JD;Morón JA
Cornichon homolog-3（CNIH 3）是一种AMPA受体（AMPAR）辅助蛋白，在背侧海马（dHPC）中显著表达，背侧海马是在空间记忆和突触可塑性中起关键作用的区域。然而，CNIH 3对AMPAR依赖性突触功能和行为的影响尚未研究。我们评估了dHPC中Cnih 3过表达的功能获得模型，并生成和表征了一系列Cnih 3 −/− C57 BL/6小鼠。我们通过行为测定、免疫印迹法测定AMPAR亚基和突触蛋白的蛋白水平以及电生理记录中的长时程增强（LTP）来评估空间记忆。我们还利用超分辨率成像工作流程SEQUIN来分析dHPC中的纳米级突触连接。在dHPC中过表达Cnih 3可以改善雌性小鼠的短期空间记忆，但在雄性小鼠中没有。与Cnih 3 +/+对照组相比，Cnih 3 −/−雌性小鼠表现出短期空间记忆减弱，dHPC突触密度降低，突触体中钙不可渗透的AMPAR（含GluA 2）亚基表达增强，LTP维持减弱; Cnih 3 −/−雄性小鼠不受影响。进一步的研究表明，在雌性Cnih 3 −/−小鼠的发情周期的后情期，空间记忆的缺陷以及AMPAR组成和突触可塑性的变化最为明显。这项研究确定了一个新的影响，性别和发情的CNIH 3的空间记忆和突触可塑性的作用。CNIH 3的操纵揭示了空间记忆、突触功能、AMPAR组成和海马可塑性的性别二态性效应。这些发现加强了将性别作为记忆和海马突触功能研究中的生物学变量的重要性。
Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3−/− C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation (LTP) in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN, for analysis of nanoscale synaptic connectivity in dHPC. Overexpression of Cnih3 in dHPC improved short-term spatial memory in female mice, but not in male mice. Cnih3−/− female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated LTP maintenance compared to Cnih3+/+ controls; Cnih3−/− males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3−/− mice. This study identified a novel effect of sex and estrous on CNIH3’s role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function.
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影响因子：
3.6
作者：
Billa, Sophie K.;Liu, Jie;Moron, Jose A.
通讯作者：
Moron, Jose A.
DOI：
10.1073/pnas.1715341114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Gerth, Fabian;Jaepel, Maria;Haucke, Volker
通讯作者：
Haucke, Volker
DOI：
10.1073/pnas.0609307104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ehrlich, Ingrid;Klein, Matthew;Malinow, Roberto
通讯作者：
Malinow, Roberto
影响因子：
7.6
作者：
Fakira, Amanda K.;Massaly, Nicolas;Moron, Jose A.
通讯作者：
Moron, Jose A.
影响因子：
1.7
作者：
Drummond, Jana B.;Simmons, Micah;Meador-Woodruff, James H.
通讯作者：
Meador-Woodruff, James H.