The role of synaptic plasticity in the pathophysiology of Parkinson's diseaseMasters in NeuroscienceModule B1: Motor SystemsCandidate Number: 325862Word Count (excluding references and figure legends): 3138Candidate Number: 3258621IntroductionLong Enhancement termination (LTP) and depression (LTD) represent two measures of synaptic plasticity, key to adaptive motor control and procedural memory. It is becoming increasingly clear that abnormalities in these processes play a key role in the pathophysiology of Parkinson's disease (PD). The purpose of this essay is to review the evidence from animal and human Parkinson's disease studies relevant to this. Critical abnormalities in striatal synaptic plasticity associated with dopaminergic loss are reviewed, combined with more recent evidence from changes in striatal postsynaptic density and N-methyl D-aspartate (NMDA) receptor subunit composition, as well as changes in the motor cortex and extrastriatal dopaminergic pathways are all noted early in the disease process. Through interesting evidence from a mouse model of Parkinson's disease, the question of whether synaptic plasticity precedes neurodegeneration in Parkinson's disease is also raised. Finding that in advanced stages of Parkinson's disease and in the context of levodopa-induced dyskinesias (LID), many of these changes become irreversible, the need for further experimental and clinical research into early Parkinson's disease in order to better understand the pathophysiology of plasticity synaptic function in Parkinson's disease is highlighted. Before that, the essay continues with a brief overview of Parkinson's disease and then LTP/LTD. Parkinson's disease is the most common neurodegenerative motor disorder, affecting 1–2% of people over the age of 60 (1). It manifests clinically with a range of motor and non-motor disorders… the focus of the article… with disorders of LTP, LTD and wasting, and these likely contribute to the clinical features of PD. Alterations in NMDA receptor subunits, postsynaptic density, and motor cortex also occur and appear to be critical in the early stages of Parkinson's disease, suggesting a potential target for early therapeutic intervention. A role for both AMPA receptors and extrastriatal dopaminergic pathways in the pathogenesis of Parkinson's disease also seems likely, but further work is needed to fully address this aspect. These disorders are generally worse in later stages of the disease and in those who develop LID, who often show no reversibility of their plasticity following dopamine administration. This highlights the need for further experimental and clinical research in early Parkinson's disease in order to better understand the pathophysiology of synaptic plasticity in Parkinson's disease. Candidate number: 32586217