HCN Channelopathy in External Globus Pallidus Neurons in Models of Parkinson’s Disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined. Following the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking that normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that plays an essential role in its generation – the HCN channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, not a cause, of key network pathophysiology – a conclusion consistent with the ability of L-type channel antagonists to attenuate silencing following DA depletion.