ALTERED BDNF AND TRKB LEVELS IN CEREBELLAR PURKINJE CELLS MAY CONTRIBUTE TO ATAXIA IN A CHRISTIANSON SYNDROME MOUSE MODEL

Ataxia is a feature of Christianson syndrome (CS), a rare X-linked neurological disorder caused by loss-of-function of the Na+/H+ exchanger NHE6. This exchanger is involved in endosomal pH control, which is essential for the trafficking of cargo, such as tropomyosin receptor kinase B (TrkB). In the hippocampus of CS mice, the Brain-Derived Neurotrophic Factor (BDNF)-TrkB pathway is dysregulated due to TrkB mistrafficking. Recently, altered BDNF-TrkB pathway has been implicated in abnormal cerebellar connectivity and ataxia. Hallmarks of ataxia are Purkinje cell (PC) firing deficits and eventual death. In CS, cerebellar development appears normal at postnatal day (P)25. PC death starts at P35 only in the anterior cerebellum, followed by ataxia at P60. Surprisingly, higher anterior and posterior PC firing rates are seen at P25. Interestingly, adding synaptic blockers abolishes these deficits, suggesting dysregulated synaptic inputs in CS cerebellum. We hypothesized that an altered BDNF-TrkB pathway causes abnormal cerebellar connectivity, leading to impaired PC activity in CS. Using immunostaining, we found higher BDNF levels in anterior and posterior PCs and higher TrkB in posterior PCs at P25. Also, increased excitatory climbing fiber inputs using vGluT2 were found on anterior and posterior PC somata at P25, suggesting their improper elimination. Together, these findings suggest that dysregulation of the BDNF-TrkB pathway could contribute to aberrant cerebellar connectivity and PC dysfunction in CS ataxia.