Anders Borgkvist

The motor symptoms of Parkinson’s disease (PD) originate from dysfunctions in the basal ganglia, triggered by a reduction in dopaminergic tone. Dopaminergic therapy is effective initially, but with time, complicated side effects emerge. Tremor and gait disturbances are refractory symptoms, partially alleviated with deep brain stimulation (DBS) therapy. In rodent and primate models of PD, we have discovered a reduction in the potassium and chloride symporter (KCC2) in the substantia nigra reticulata (SNr), a promising DBS target for reducing freezing of gait in PD. This disruption causes impaired GABAergic inhibition of SNr, which may underlie problems in movement initiation. We hypothesize that DBS enhances KCC2 expression, suggesting KCC2-enhancing drugs as new therapeutic alternatives in PD. Firstly, we will examine how KCC2 regulates synaptic integration in SNr neurons. Next, we will determine if DBS of SNr inputs reduces parkinsonism by restoring KCC2 functionin a mouse model of PD. In parallel, by stimulating the subthalamic nucleus, we will determine if the reduction in KCC2 is triggered by glutamate release. Finally, we will examine the antiparkinsonian effect of drugs promoting KCC2 function using behavioral analyses. Recovery of synaptic function in the SNr will be examined by measuring SNr activity in mice with fiber photometry and GCaMP imaging. Altogether, this project investigates a new therapeutic option that may promote non-dopaminergic medications in PD.