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 manipulati...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;BOD1f/f mice.Together,these findings further suggest that specific regulation of the cerebellar IV/V lobePCs→FNCaMKIIα+circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.展开更多
基金funded by the National Natural Science Foundations of China(grant no.81973300 to YML,grant no.82104162 to X.X.L.and grant no.81803506 to Q.J.)the State Key Program of National Natural Science Foundations of China(grant no.81930103 to F.H.).
文摘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;BOD1f/f mice.Together,these findings further suggest that specific regulation of the cerebellar IV/V lobePCs→FNCaMKIIα+circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
