ROBUSTEX

Robustness is a general feature of complex evolvable biological systems. It is defined as the ability of a complex system to maintain function in the face of internal and external perturbations. The mammalian nervous sytem for instance is in some respect surprisingly robust to perturbations: post-lesional recovery or the preclinical asymptomatic phase of Parkinson’s disease are two expressions of this robustness. Ultimately, cognitive and behavioral robustness relies on the ability of single neurons to maintain information transfer constant. Unraveling the principles underlying the robustness of neuronal activity therefore seems critical to our understanding of the physiology and physiopathology of the nervous system. In the current proposal, we will study the biophysical principles underlying robustness of neuronal activity in the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) of the mouse using electrophysiological and immunohistochemical approaches. We will particularly focus on how these neurons maintain a regular pacemaking activity and action potential shape and energy efficiency. To do so, we intend to study these firing properties in both unperturbed conditions (wild-type mice) and perturbed conditions (deletion of the gene for the Cav1.3 calcium channel). In particular, we want to determine the regulatory rules linking the Cav1.3 channel to the HCN and Kv4.3 channels. These three channels play major roles in the genesis of pacemaking activity in SNc DA neurons. In spite of its demonstrated role in pacemaking, the absence of the Cav1.3 channel does not significantly modify pacemaking, demonstrating remarkable compensation by other types of ion channels. Our personal data and the published literature suggest that a dynamic regulation of the properties of HCN and Kv4.3 channels is involved in this compensation. Moreover, although pacemaking is maintained in the Cav1.3 KO mouse, it is unclear whether action potential shape is maintained. This is an important point since the action potential consumes a very significant part of the energy budget of neurons, and action potential shape has been related to its energy efficiency. Moreover, alterations in cell metabolism have been proposed to play a role in the neurodegeneration of specific subpopulations of SNc DA neurons. We will investigate whether the energy efficiency is maintained in the Cav1.3 KO mouse, but will also investigate whether SNc DA neurons all produce action potentials with similar energy efficiency in wild-type animals, or whether the energy efficiency of the action potential can be related to specific subpopulations of SNc DA neurons. In this part of the project, we will focus on the currents underlying the action potential to determine whether specific regulatory rules ensure that action potential shape and energy efficiency is maintained in the face of perturbations such as ion channel deletion or variation. We believe that deciphering the rules underlying robustness of pacemaking and action potential shape in SNc DA neurons may have implications for our understanding of robustness of neuronal activity in general, but also for our understanding of the physiopathology of these neurons.