NAV1.2 DELETION CAUSES MORPHOLOGY AND EXCITABILITY ALTERATIONS IN MOUSE SUBSTANTIA NIGRA DOPAMINERGIC NEURONS

Dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) produce pacemaker activity and display faithful back-propagation of the action potential (AP). Morphologically, these neurons are characterized by the emergence of the axon from a dendrite (the axon-bearing dendrite or ABD). Previous studies demonstrated that the excitability and morphology of the dendrites directly influence electrophysiological features, due in particular to the presence of a high density of dendritic sodium channels. However, the identity of these dendritic sodium channels is still unknown. In the present study, we used Nav1.2/DAT-Cre KO mice to determine whether Nav1.2 sodium channels could be involved in dendritic excitability in SNc DA neurons. We performed whole-cell recordings to characterize the electrophysiological phenotype followed by post-hoc neuronal reconstruction to describe the morphology of SNc DA neurons, including dendritic morphology and axon initial segment (AIS) geometry. Nav1.2 KO neurons showed decreased spontaneous activity, as well as altered AP shape (decrease in amplitude, increase in half-width, decrease in rising slope), demonstrating altered dendritic excitability. Importantly, they also exhibited significant alterations in AIS morphology and dendritic topology: the AIS was located closer to the soma and its length was increased, while the complexity of the non-ABDs was increased. In summary, deleting Nav1.2 from SNc DA neurons has a strong impact on both their dendritic morphology and excitability, and consequently on their spontaneous activity and AP waveform. However, while some electrophysiological modifications might be a direct consequence of the observed alterations in morphology, others suggest hidden biophysical and/or morphological compensatory mechanisms.