Bcl11a deficiency in cerebellar Purkinje cells causes ataxia and autistic-like behavior by altering Vav3.

BCL11A encodes a transcription factor essential for brain development, with pathogenic variants causing intellectual disability, autism spectrum disorder (ASD), microcephaly, hypotonia, and behavioral abnormalities. While clinical studies have identified cerebellar pathology in patients with BCL11A variants, the specific roles of this gene in cerebellar function and its relationship to clinical symptoms remain unclear. In this study, we demonstrate that Bcl11a is predominantly expressed in Purkinje cells (PCs) of both the developing and adult mouse cerebellum. Conditional deletion of Bcl11a in PCs leads to impaired PC survival, disrupts dendritic morphology, reduces spine density, and results in ataxia, motor learning deficits, and autistic-like behaviors. Electrophysiological analyses reveal that Bcl11a-deficient PCs exhibit decreased frequency and regularity of spontaneous firing and reduced excitatory synaptic inputs from both parallel and climbing fibers, while maintaining normal intrinsic excitability and inhibitory synaptic inputs. Moreover, we identify Vav3 (guanosine nucleotide exchange factor 3) as a downstream target of Bcl11a in PCs and demonstrate that Vav3 overexpression partially rescues both PC dysfunction and abnormal motor and social behaviors in Bcl11a-deficient mice. Together, these findings establish Bcl11a's critical role in PC function and provide mechanistic insight into how BCL11A mutations contribute to cerebellar dysfunction in psychiatric disorders such as ASD.