Role of Nav1.1 and Nav1.2 ion channels in dopaminergic neuron activity

The midbrain dopaminergic neurons display several electrophysiological peculiarities: i) they generate a pacemaker activity (autonomous tonic regular pattern of activity) in the absence of synaptic inputs, in vitro and in vivo ii) their action potential faithfully back-propagates through the entire dendritic tree without attenuation, which allows iii) dopamine release at dendro-dendritic synapses. As a consequence, sodium channels expressed in the dendrites of these neurones play a particularly critical role since they participate in the genesis of pacemaker activity and are fully responsible for the back-propagation of the action potential. Several studies performed in our group (Tapia et al., Sci. Rep. 2018; Moubarak et al., J. Neurosci, 2019, 2022) suggest that Nav1.2 channels are the main subtype expressed in the dendrites, although Nav1.1 channels could also be expressed. To answer this question, we propose to use transgenic mice carrying a deletion of Nav1.1 or Nav1.2 specifically in dopaminergic neurons (Cre/lox constructs). Our preliminary results seem to confirm our main hypothesis, since dopaminergic neurons from Nav1.2+/- monoallelic animals display significant alterations in the shape of their action potential. The Master internship project willd be to characterize the electrophysiological modifications in dopaminergic neurons from Nav1.2-/- and Nav1.1-/- transgenic mice. This project will shed light on the molecular basis of rhythmogenicity in this neuronal type. Given the postulated links between the pathological vulnerability of midbrain dopaminergic neurons (in Parkinson’s disease in particular) and their peculiar electrophysiological phenotype, reaching a better understanding of the pacemaking mechanisms could provide a better understanding of their premature degeneration in pathological contexts.

The applicant should have a solid knowledge in cellular and molecular neuroscience, in particular in ion channel biophysics and neuronal excitability. A practical experience in cellular electrophysiology would be a bonus.

The SANE team (Systems Approaches to Neuronal Excitability) is part of the INT (Institut de Neurosciences de la Timone), a neuroscience laboratory located on the Campus Timone. INT is a laboratory comprised of 13 teams working on various aspects of neuroscience and using diverse approaches, from molecular, genetic approaches to behavioral studies to study brain at the microscopic, mesoscopic and macroscopic levels. INT host a large number of PhD and post-doctoral candidates (40-60) and a specific committee (SYRT) driving young researchers interactions.