Venue: ENSTBB, Campus Carreire
Jakob Scharnholz
IMN
Title
Study of electrophysiological and behavioral alterations in a prodromal model of Parkinson’s disease
Abstract
Parkinson’s Disease (PD) is characterized by the degeneration of dopaminergic neurons (DAN) of the substanita nigra pars compacta (SNc) and subsequent dopamine depletion in the dorsal striatum (DS). Cardinal motor symptoms such as bradykinesia, resting tremor, and postural rigidity are caused by nigral dopamine deficiency but typically manifest only after neuronal loss of more than 60 \% of nigral DAN. Dopamine dysfunction has been suggested to occur years before diagnosis. However, there is so far little functional evidence for this hypothesis. Using a mouse model displaying aggregated forms of alpha-synuclein (a-syn) , mimicking the most common co-pathology to degeneration that readily manifests prior to neuronal loss, we investigate nigrostriatal circuit function in a prodromal disease context. Intrastriatal injection of recombinant a-syn pre-formed fibrils initiated endogenous aggregation of mouse a-syn in the striatum, spreading to the SNc without inducing gross motor deficits or DAN loss. We observed an a-syn aggregation-dependent reduction of firing properties of DAN only at 4 monhts post injection (MPI), although nigral aggregates were already detectable at 2 MPI. Already from 2 MPI, reward-related phasic striatal dopamine release in a reaching task was moderately reduced, while synchronized spillover striatal dopamine release as well as striatal TH staining were not altered. We additionally identified a convergence of excitability that could be viewed as a cellular identity loss between direct and indirect spiny projection neurons that could be sufficient to counterbalance dopaminergic alterations and maintain cortico-striatal integration, thus explaining maintenance of motor function integrity. This thesis provides strong evidence that a-syn aggregation triggers early nigrostriatal alterations of dopaminergic function, well in advance of the appearance of gross motor deficits that occur only when DAN loss is consequent.
Key words
Prodromal Parkinson’s Disease, alpha-synuclein, dopaminergic neuron, dopaminergic transmission, motor deficits, spiny projecting neuron