Excitatory/inhibitory imbalance in Parkinson’s disease LRRK2-associated

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Alteration of striatum projections leads to severe motor deficits. Besides, non-motor symptoms can arise even many years before the diagnosis. The existence of the premotor stage provides a potential temporal window to work in favour of preventing or deleing the progression of disease. Leucine-rich repeat kinase 2 (LRRK2) has been discovered to play a role in both monogenic and sporadic forms of PD, in which the substitution Gly2019Ser has been observed at a high frequency. LRRK2 takes part in many cellular processes including vesicular trafficking, mitochondrial process, lysosomal functions, and cytoskeleton dynamic but many other mechanisms have yet to be better understood. My PhD project aimed to investigate the role of LRRK2 on excitatory/inhibitory (E/I) imbalance displayed by PD patients. Glutamate and GABA neurotransmitters are mainly involved in controlling the E/I balance of the neurons; consequently, changes in glutamatergic and GABAergic circuits could influence the neuronal networks causing aberrant synaptic signalling. Therefore, we studied the relation between LRRK2 and excitatory/inhibitory actors mainly involved in neural communication to provide new insights into molecular mechanisms that can help to intervene during the premotor stage of disease, preventing or deleing neurodegeneration.