Signalling pathways in autism spectrum disorder:mechanisms and therapeutic implications

Autism spectrum disorder(ASD)is a prevalent and complex neurodevelopmental disorder which has strong genetic basis.Despite the rapidly rising incidence of autism,little is known about its aetiology,risk factors,and disease progression.There are currently neither validated biomarkers for diagnostic screening nor specific medication for autism.Over the last two decades,there have been remarkable advances in genetics,with hundreds of genes identified and validated as being associated with a high risk for autism.The convergence of neuroscience methods is becoming more widely recognized for its significance in elucidating the pathological mechanisms of autism.Efforts have been devoted to exploring the behavioural functions,key pathological mechanisms and potential treatments of autism.Here,as we highlight in this review,emerging evidence shows that signal transduction molecular events are involved in pathological processes such as transcription,translation,synaptic transmission,epigenetics and immunoinflammatory responses.This involvement has important implications for the discovery of precise molecular targets for autism.Moreover,we review recent insights into the mechanisms and clinical implications of signal transduction in autism from molecular,cellular,neural circuit,and neurobehavioural aspects.Finally,the challenges and future perspectives are discussed with regard to novel strategies predicated on the biological features of autism.

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.

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.