Imbalances behind Parkinson’s disease – the role of interneurons
The golden age of basal ganglia research has taught scientists one essential thing about Parkinson’s disease: its symptoms all arise from an imbalance between two neural pathways in our brain, called the direct and indirect pathways of the basal ganglia. This imbalance, which is elaborated by the so-called box-and-arrow model, is caused by the loss of dopamine innervation to these pathways. But there are other, less understood phenomena at play. “We know that under normal conditions, the dopaminergic innervation of these pathways is complemented by innervation with another neuromodulator called acetylcholine. Acetylchoine is provided by an important class of cholinergic interneurons (CINs) which exert a powerful influence over these pathways, so we argue that in order to fully understand the changes that occur in these pathways after the loss of dopamine, we must understand how this loss of dopamine directly affects the CINs,” says Dr Joshua Goldberg, PhD at the Department of Medical Neurobiology of the Hebrew University of Jerusalem. This was the purpose of the BurstPausePlasticity project. Together with his team, Dr Goldberg used optogenetics – a molecular tool developed to enable the activation of neural pathways with light pulses – to activate the various excitatory inputs to the CINs. Once done, they compared the effects of DA loss on excitatory neuronal input from the neocortex and the thalamus, the two sources of excitatory neuronal input driving the two BG pathways. “Our study illuminates how the impact of DA loss on the excitatory input to CINs complements its direct impact on the excitatory input to the two BG pathways. We found that while neocortical input to CINs is not affected, their thalamic input is weakened by dopamine loss,” explains Dr Goldberg. These findings suggest that the imbalance formed between the BG pathways is actually exacerbated by the alteration in thalamic input to CINs. Besides, these alterations are pathway selective: Only the thalamic input was impacted, while the neocortical pathway was not. “The adaptation we observed might contribute to the akinesia (the difficulty to initiate movement) brought on by Parkinson’s Disease. Because this link from the thalamus to CINs is important for behavioral flexibility, the observed weakening of this pathway may affect the akinetic state,” Dr Goldberg points out. Project findings also imply that considering how individual neurons are affected is not enough to understand the impact of a neurodegenerative process. The whole network of neurons needs to be taken into consideration, and the alterations show how the network as an entity of its own adapts, sometimes impacting one link in the circuit without impacting the other. With the project now completed, Dr Goldberg is currently using ERC funding to investigate how CINs form assemblies during normal behavior and how they are affected under parkinsonian conditions. “We use microendoscopes (miniaturised fluorescent microscopes) to image brain activity in freely moving subjects. Because CINs have been recently implicated in another serious complication of PD – the dyskinesias (uncontrollable shuffling movements) caused by dopamine replacement therapy (DRT) – we hope to better understand how the behavior of the network of CINs changes with the development of dyskinesias,” he explains. Dr Goldberg hopes that, eventually, his work will contribute to the development of more efficient therapies leading to less unwanted side effects of DRT.
Keywords
BurstPausePlasticity, Parkinson’s disease, basal ganglia, dopamine, cholinergic interneurons, CINs, BG pathways