Cerebellar glutamatergic system impacts spontaneous motor recovery by regulating Gria1 expression

Abstract

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.

Real‐time field‐programmable gate array‐based closed‐loop deep brain stimulation platform targeting cerebellar circuitry rescues motor deficits in a mouse model of cerebellar ataxia

“…EMG movement‐triggering closed‐loop DBS system has been used to close the loop in essential tremor and performed better than the tremor‐modulated closed‐loop DBS system even though the EMG movement‐triggering system will still trigger stimulation when the patients make movement that do not result in tremor 55 . Motor function depends on the integrity of descending motor pathways that ultimately activate target muscles 31,56 . We recently reported that disruption of cerebellothalamocortical motor circuitry in ataxia mice significantly delays EMG onset and reduces EMG amplitude after electrical or optogenetic DCN stimulation, suggesting an alternation of cerebellar outputs due to the disruption of spinal motor circuits, resulting in reduced motor activity 31 .…”

“…Motor function depends on the integrity of descending motor pathways that ultimately activate target muscles 31,56 . We recently reported that disruption of cerebellothalamocortical motor circuitry in ataxia mice significantly delays EMG onset and reduces EMG amplitude after electrical or optogenetic DCN stimulation, suggesting an alternation of cerebellar outputs due to the disruption of spinal motor circuits, resulting in reduced motor activity 31 . Several clinical reports suggest that chronic muscle denervation is a sign of PD, for which EMG tests play a critical diagnostic role 57,58 .…”

“…To address these issues, use of a FPGA-based platform in BCI devices and closedloop controls have been reported. [46][47][48] Electromyography recording allows detection of functional neuromuscular synapses at target muscles and is widely used to quantify motor function recovery 29,31,34,[50][51][52] and motor deficits in movement disorders. For instance, surface EMG (sEMG) from symptomatic extremities can be used to predict the onset of tremor in essential tremor patient 53 with an accuracy of over 80% in PD and essential tremor patients.…”

“…31,56 We recently reported that disruption of cerebellothalamocortical motor circuitry in ataxia mice significantly delays EMG onset and reduces EMG amplitude after electrical or optogenetic DCN stimulation, suggesting an alternation of cerebellar outputs due to the disruption of spinal motor circuits, resulting in reduced motor activity. 31 Several clinical reports suggest that chronic muscle denervation is a sign of PD, for which EMG tests play a critical diagnostic role. 57,58 Although beta power in the subthalamic nucleus (STN) is a useful metric in PD, beta oscillations, while linked to clinical symptoms, are modulated by external factors like medication, movement, speaking, and cognition.…”

“…Mice were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg) for customized electrode implantation into the GCM as described previously. 29,[31][32][33] Briefly, a 1-cm incision on the head was made and the electrode connector was affixed to the skull with dental cement. The wire between the electrode connector and GCM was inserted subcutaneously from the dorsal neck to the leg.…”