Striatal CDK5 Regulates Cholinergic Neuron Activation and Dyskinesia-like Behaviors through BK Channels

Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance remain elusive.Here,we showed that cyclin-dependent kinase 5(Cdk5)was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis.Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms.Moreover,Cdk5 deficiency in cholinergic neurons triggered paw tremors,abnormal motor coordination,and motor balance deficits in mice.These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+channels(BK channels).Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice.Furthermore,CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908.Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice.Together,these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuronmediated motor function,providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.

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 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.

Multiregional neural pathway: from movement planning to initiation

A recent study by Inagaki et al.provides new evidence that the input from the pedunculopontine nucleus/midbrain reticular nucleus(PPN/MRN)to the thalamus can trigger a rapid switch of ALM activity from a motor planning mode to a motor execution mode.1 Planning and execution are vital components of motor behavior that are produced by distinct patterns of neuronal activity.Neuroscience researchers have devoted substantial effort to exploring how the precise neural pathway mediates cuetriggered population activity pattern switching for the execution of planned movements.The different patterns of neuronal population activity in the motor cortex,thalamus,brainstem,and spinal cord are related to motor planning and execution.2,3 However,to understand how neuronal dynamics in the cortex trigger motor execution,it is essential to explore the mechanism underlying the transition between those different modes in response to contextual Go cues(Fig.1).