TY - JOUR
T1 - Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex
AU - Gawande, Dinesh Y.
AU - Kishore, Kishore Kumar
AU - Bhatt, Jay M.
AU - Pavuluri, Ratnamala
AU - Kesherwani, Varun
AU - Suryavanshi, Pratyush S.
AU - Shelkar, Gajanan P.
AU - Dravid, Shashank M.
N1 - Funding Information:
This work was supported by grants from the NSF1456818 (SMD), NIH NS104705 (SMD), NIH NS118731 (SMD) and NIH MH116003 (SMD).
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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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U2 - 10.1016/j.phrs.2022.106144
DO - 10.1016/j.phrs.2022.106144
M3 - Article
C2 - 35304260
AN - SCOPUS:85126727110
VL - 178
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
M1 - 106144
ER -