Cerebellar climbing fibers in neurodevelopmental disorders

The cerebellum is increasingly recognized for its involvement in various neurodevelopmental disorders with deficits in motor and cognitive functioning. In this review, we highlight recent advances in our understanding of abnormal olivocerebellar climbing fiber development in various preclinical models for these disorders. The cerebellum undergoes extensive postnatal development, during which climbing fibers from the inferior olive establish and refine synaptic connections with Purkinje cells, the principal neurons of the cerebellar cortex. Initially, each Purkinje cell receives input from multiple climbing fibers, but developmental synapse elimination ultimately produces a precise one-to-one connection. Increasing evidence indicates that faulty cerebellar circuit formation and function can arise from aberrant climbing fiber development, such as defects in synapse elimination, dendritic translocation, synaptic structure, synaptic number, or neurotransmission. Multiple studies have identified aberrant climbing fiber development in neurodevelopmental and neurological disorders, including autism spectrum disorder, schizophrenia, ataxia, dystonia, and essential tremor. We summarize the cellular and molecular mechanisms governing climbing fiber development and examine how their disruption contributes to disease pathogenesis. This work highlights the olivocerebellar circuit as a critical determinant of typical brain development and neurological function that is often disrupted in neurodevelopmental disorders.