TY - JOUR
T1 - Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression
AU - Asthana, Pallavi
AU - Kumar, Gajendra
AU - Milanowski, Lukasz M.
AU - Au, Ngan Pan Bennett
AU - Chan, Siu Chung
AU - Huang, Jianpan
AU - Feng, Hemin
AU - Kwan, Kin Ming
AU - He, Jufang
AU - Chan, Kannie Wai Yan
AU - Wszolek, Zbigniew K.
AU - Ma, Chi Him Eddie
PY - 2022/9/5
Y1 - 2022/9/5
N2 - Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.
AB - Peripheral nerve injury (PNI) often results in spontaneous motor recovery; however, how disrupted cerebellar circuitry affects PNI-associated motor recovery is unknown. Here, we demonstrated disrupted cerebellar circuitry and poor motor recovery in ataxia mice after PNI. This effect was mimicked by deep cerebellar nuclei (DCN) lesion, but not by damaging non-motor area hippocampus. By restoring cerebellar circuitry through DCN stimulation, and reversal of neurotransmitter imbalance using baclofen, ataxia mice achieve full motor recovery after PNI. Mechanistically, elevated glutamate-glutamine level was detected in DCN of ataxia mice by magnetic resonance spectroscopy. Transcriptomic study revealed that Gria1, an ionotropic glutamate receptor, was upregulated in DCN of control mice but failed to be upregulated in ataxia mice after sciatic nerve crush. AAV-mediated overexpression of Gria1 in DCN rescued motor deficits of ataxia mice after PNI. Finally, we found a correlative decrease in human GRIA1 mRNA expression in the cerebellum of patients with ataxia-telangiectasia and spinocerebellar ataxia type 6 patient iPSC-derived Purkinje cells, pointing to the clinical relevance of glutamatergic system. By conducting a large-scale analysis of 9,655,320 patients with ataxia, they failed to recover from carpal tunnel decompression surgery and tibial neuropathy, while aged-match non-ataxia patients fully recovered. Our results provide insight into cerebellar disorders and motor deficits after PNI.
UR - http://www.scopus.com/inward/record.url?scp=85137827752&partnerID=8YFLogxK
U2 - 10.1038/s41536-022-00243-6
DO - 10.1038/s41536-022-00243-6
M3 - Article
AN - SCOPUS:85137827752
SN - 2057-3995
VL - 7
JO - npj Regenerative Medicine
JF - npj Regenerative Medicine
IS - 1
M1 - 45
ER -