Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.
Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.
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DOI：
10.1016/j.phrs.2022.106144
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发表时间：
2022-04
影响因子：
9.3
通讯作者：
Dravid, Shashank M.
中科院分区：
文献类型：
--
作者：
Gawande, Dinesh Y.;Narasimhan, Kishore Kumar S.;Bhatt, Jay M.;Pavuluri, Ratnamala;Kesherwani, Varun;Suryavanshi, Pratyush S.;Shelkar, Gajanan P.;Dravid, Shashank M.
谷氨酸受体δ家族由GluD1和GluD2组成，并作为突触组织者。我们以前已经证明了几个自闭症样的分子和行为表型，包括增加树突棘GluD1敲除小鼠。基于以前的报道，我们评估了自噬机制的破坏是否可以解释这些表型。利用皮质边缘区兴奋性神经元GluD1条件性缺失的小鼠模型。GluD1缺失导致Akt-mTOR通路过度活跃，躯体感觉皮层中p62升高和LC3-II/LC3-I比值降低，表明自噬减少。兴奋性元件的数量增加，但具有不成熟的表型的基础上斑点的大小，较低的AMPA亚基GluA1表达和受损的发展开关，从主要GluN2B混合GluN2A/GluN2B亚基表达。过度活跃的Akt-mTOR信号转导和受损的自噬也观察到背侧纹状体后，条件性消融GluD1和组成性敲除的前额叶皮层和海马。最后，在皮质边缘区GluD1条件性消融的小鼠中观察到新物体识别测试和恐惧条件反射的认知缺陷。总之，这些结果证明了GluD1在调节自噬途径中的新功能，这可能是自闭症表型的基础，并与GluD1编码，GRID1基因与自闭症和其他发育障碍的遗传关联有关。
The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes. Mouse model with conditional deletion of GluD1 from excitatory neurons in the corticolimbic regions was utilized. GluD1 loss led to overactive Akt-mTOR pathway, higher p62 and a lower LC3-II/LC3-I ratio in the somatosensory cortex suggesting reduced autophagy. Excitatory elements were increased in number but had immature phenotype based on puncta size, lower AMPA subunit GluA1 expression and impaired development switch from predominantly GluN2B to mixed GluN2A/GluN2B subunit expression. Overactive Akt-mTOR signaling and impaired autophagy was also observed in dorsal striatum upon conditional ablation of GluD1 and in the prefrontal cortex and hippocampus in constitutive knockout. Finally, cognitive deficits in novel object recognition test and fear conditioning were observed in mice with conditional ablation of GluD1 from the corticolimbic regions. Together, these results demonstrate a novel function of GluD1 in the regulation of autophagy pathway which may underlie autism phenotypes and is relevant to the genetic association of GluD1 coding, GRID1 gene with autism and other developmental disorders.
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影响因子：
4.7
作者：
Gupta SC;Yadav R;Pavuluri R;Morley BJ;Stairs DJ;Dravid SM
通讯作者：
Dravid SM
影响因子：
21.3
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通讯作者：
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影响因子：
11
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Benamer N;Marti F;Lujan R;Hepp R;Aubier TG;Dupin AAM;Frébourg G;Pons S;Maskos U;Faure P;Hay YA;Lambolez B;Tricoire L
通讯作者：
Tricoire L
影响因子：
56.9
作者：
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通讯作者：
Yuzaki, Michisuke
影响因子：
16.2
作者：
Fossati, Matteo;Assendorp, Nora;Charrier, Cecile
通讯作者：
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