Abstract

Disturbed motor control is a hallmark of Parkinson´s Disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and BDNF from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny neurons (MSNs). We studied the role of dopamine in modulating sensitivity of MSNs to BDNF in cultures of FACS enriched D1 expressing MSNs (dMSNs) and 6-OHDA treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dMSN neurons, 6-OHDA treated rats and patient postmortem brain reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with SORCS-2 in multivesicular like structures which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing contributes to disturbed motor function and interference with abnormal processing of TrkB in the ER may provide therapeutic benefit in PD.