Gawande Dinesh Y, S Narasimhan Kishore Kumar, Bhatt Jay M, Pavuluri Ratnamala, Kesherwani Varun, Suryavanshi Pratyush S, Shelkar Gajanan P, Dravid Shashank M
Department of Pharmacology and Neuroscience, Creighton University, 2500 California Plaza, Omaha, NE, USA.
Department of Pharmacology and Neuroscience, Creighton University, 2500 California Plaza, Omaha, NE, USA.
Pharmacol Res. 2022 Apr;178:106144. doi: 10.1016/j.phrs.2022.106144. Epub 2022 Mar 15.
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.
谷氨酸受体δ家族由GluD1和GluD2组成，作为突触组织者。我们之前已经证明了几种类似自闭症的分子和行为表型，包括GluD1基因敲除小鼠树突棘增加。基于之前的报道，我们评估了自噬机制的破坏是否可能导致这些表型。我们使用了在皮质边缘区域的兴奋性神经元中条件性缺失GluD1的小鼠模型。GluD1的缺失导致体感皮层中Akt-mTOR通路过度活跃、p62水平升高以及LC3-II/LC3-I比率降低，提示自噬减少。基于突触后致密斑大小、AMPA亚基GluA1表达降低以及从主要为GluN2B向混合的GluA1/GluN2B亚基表达的发育转换受损，兴奋性元件数量增加但具有不成熟的表型。在条件性切除GluD1的背侧纹状体以及组成型敲除小鼠的前额叶皮层和海马体中也观察到Akt-mTOR信号过度活跃和自噬受损。最后，在皮质边缘区域条件性切除GluD1的小鼠中，在新物体识别测试和恐惧条件反射中观察到认知缺陷。总之，这些结果证明了GluD1在自噬途径调节中的新功能，这可能是自闭症表型的基础，并且与GluD1编码基因GRID1与自闭症和其他发育障碍的遗传关联相关。
