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BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156688/ https://www.ncbi.nlm.nih.gov/pubmed/35641478 http://dx.doi.org/10.1038/s41392-022-00989-x |
Sumario: | Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα(+) neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα(+) neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1(f/f) mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobe(PCs )→ FN(CaMKIIα+) circuit might provide neuromodulatory targets for the treatment of ataxia behaviors. |
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