Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex

神经科学 谷氨酸受体 兴奋性突触后电位 海马体 PI3K/AKT/mTOR通路 条件基因敲除 前额叶皮质 自噬 表型 体感系统 生物 AMPA受体 树突棘 细胞生物学 化学 受体 信号转导 抑制性突触后电位 基因 遗传学 认知 海马结构 细胞凋亡
作者
Dinesh Y. Gawande,Kishore Kumar S Narasimhan,Jay M. Bhatt,Ratnamala Pavuluri,Varun Kesherwani,Pratyush S. Suryavanshi,Gajanan P. Shelkar,Shashank M. Dravid
出处
期刊:Pharmacological Research [Elsevier BV]
卷期号:: 106144-106144 被引量:1
标识
DOI:10.1016/j.phrs.2022.106144
摘要

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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