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Differential Robustness to Specific Potassium Channel DIFFERENTIAL ROBUSTNESS TO SPECIFIC POTASSIUM CHANNEL DELETIONS IN MIDBRAIN DOPAMINERGIC NEURONS Alexis Haddjeri-Hopkins, Béatrice Marqueze-Pouey, Monica Tapia, Fabien Tell, Marianne Amalric, Jean-Marc Goaillard To cite this version: Alexis Haddjeri-Hopkins, Béatrice Marqueze-Pouey, Monica Tapia, Fabien Tell, Marianne Amalric, et al.. DIFFERENTIAL ROBUSTNESS TO SPECIFIC POTASSIUM CHANNEL DELETIONS IN MIDBRAIN DOPAMINERGIC NEURONS. 2020. hal-03026595 HAL Id: hal-03026595 https://hal.archives-ouvertes.fr/hal-03026595 Preprint submitted on 26 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. DIFFERENTIAL ROBUSTNESS TO SPECIFIC POTASSIUM CHANNEL DELETIONS IN MIDBRAIN DOPAMINERGIC NEURONS Alexis HADDJERI-HOPKINS1, Béatrice MARQUEZE-POUEY1, Monica TAPIA1, Fabien TELL1, Marianne AMALRIC2 and Jean-Marc GOAILLARD1, 3 1 UMR_S 1072, Aix Marseille Université, INSERM, Faculté de Médecine Secteur Nord, Marseille, FRANCE 2 Aix Marseille Université, CNRS, LNC, FR3C, Marseille, FRANCE 3 Corresponding author Author contributions : M.A. and J-M.G. designed research. A.H-H., B.M-P. and M.T. performed research. A.H-H., B.M-P., M.T. and F.T. analyzed data. A.H-H., F.T., M.A. and J-M.G. wrote the manuscript. Corresponding author: Jean-Marc GOAILLARD. UMR_S 1072, Aix Marseille Université, INSERM, Faculté de Médecine Secteur Nord, Marseille, FRANCE. Email: [email protected] Conflict of interest The authors declare no competing interests. 1 Abstract Quantifying the level of robustness of neurons in ion channel knock-out (KO) mice depends on how exhaustively electrical phenotype is assessed. We characterized the variations in behavior and electrical phenotype of substantia nigra pars compacta (SNc) dopaminergic neurons in SK3 and Kv4.3 potassium channel KOs. SK3 and Kv4.3 KO mice exhibited a slight increase in exploratory behavior and impaired motor learning, respectively. Combining current-clamp characterization of 16 electrophysiological parameters and multivariate analysis, we found that the electrical phenotype of SK3 KO neurons was not different from wild-type neurons, while that of Kv4.3 KO neurons was significantly altered. Consistently, voltage-clamp recordings of the underlying currents demonstrated that the SK current charge was unchanged in SK3 KO neurons while the Kv4-mediated A-type current was virtually abolished in Kv4.3 KO neurons. We conclude that the robustness of SNc dopaminergic neurons to potassium channel deletions is highly variable, due to channel-specific compensatory mechanisms. 2 INTRODUCTION Is the electrical phenotype of neurons robust to ion channel deletion, and what are the rules that define the level of robustness ? Until recently, the absence of a clear phenotype when artificially mutating or deleting a given gene was often taken as evidence for lack of functional relevance, and many studies based on genetically- modified animals with "negative phenotypes" have probably never been published (Barbaric et al, 2007; Edelman & Gally, 2001). However, it is now accepted that biological systems have ways of coping with gene mutation or deletion, especially through functional redundancy and pleiotropy of the genes (Kirschner & Gerhart, 1998; Kitano, 2004; Klassen et al, 2011). Studying transgenic animals with negative phenotypes is therefore a unique way of gaining insights into the molecular mechanisms underlying the astonishing robustness of biological systems. Ion channels, in particular voltage-dependent ion channels, constitute a striking example of functional redundancy (Amendola et al, 2012; Marder & Goaillard, 2006; Taylor et al, 2009). Indeed, in most neuronal types, many different subtypes of voltage-dependent ion channels are expressed, far more than the theoretical minimum needed to generate the appropriate pattern of activity (Podlaski et al, 2017; Prinz et al, 2004). Consistently, computational studies have demonstrated that ion channel redundancy underlies the multiplicity of biophysical solutions that can confer a given electrical phenotype (Drion et al, 2015; O'Leary et al, 2014; Taylor et al, 2009). As an unsurprising consequence, a number of studies have now demonstrated that the phenotype of ion channel knock-outs (KOs) is often far from what can be expected based on acute blockade of ion channels (Carrasquillo et al, 2012; Kulik et al, 2019; Nerbonne et al, 2008; Swensen & Bean, 2005), suggesting that compensatory 3 mechanisms are at play. However, the depth of phenotype characterization determines how well its variations or stability are assessed, such that negative phenotypes might sometimes be the result of an under-assessment of neuronal function (Barbaric et al, 2007). The Kv4.3 potassium channel and the small-conductance calcium-activated potassium channel 3 (SK3) are widely expressed in several brain areas (Serodio & Rudy, 1998; Vacher et al, 2006) and in several cardiac tissues, including the pacemaker node (Kv4.3) (Serodio et al, 1996). In spite of this, previous reports suggested that the SK3 and Kv4.3 KO mice do not display an overt phenotype (Carrasquillo et al, 2012; Jacobsen et al, 2008; Nerbonne et al, 2008). Interestingly, both of these ion channels are strongly expressed in SNc DA neurons and play important roles in the control of their pattern of activity (Amendola et al, 2012; de Vrind et al, 2016; Deignan et al, 2012; Hahn et al, 2003; Liss et al, 2001; Serodio & Rudy, 1998; Seutin et al, 1993; Vandecasteele et al, 2011; Wolfart et al, 2001; Wolfart & Roeper, 2002). Specifically, the Kv4.3 ion channel is responsible for the A-type potassium current controlling spontaneous firing frequency and post-inhibitory rebound (Amendola et al, 2012; Hahn et al, 2003; Liss et al, 2001), while the SK3 channel is involved in the control of firing regularity and excitability (Deignan et al, 2012; Wolfart et al, 2001). SNc DA neurons project onto the dorsal striatum (forming the nigrostriatal pathway) where they release DA. As a consequence, their activity has been demonstrated to critically influence motor learning, habitual and goal-directed actions (Balleine, 2019; Wise, 2004; Yin & Knowlton, 2006). We used behavioral tests to address alterations in motor activity and motor learning, and current-clamp and voltage-clamp electrophysiology to evaluate the robustness of the SNc DA neuron phenotype to the deletion of SK3 and Kv4.3 channels. In 4 addition, following the approach developed in a previous study (Dufour et al, 2014a), we used multivariate analysis of current clamp-recorded parameters to evaluate global alterations in electrical phenotype. While the loss of Kv4.3 ion channel does not seem to be compensated at all, genetic deletion of SK3 is associated with very slight variations in electrical phenotype of these neurons. The comparison of phenotype variations after chronic deletion or acute pharmacological blockade of these channels allowed us to quantify the precise level of robustness of SNc DA neurons to the deletion of Kv4.3 and SK3, respectively. Voltage-clamp experiments suggest that Kv4.3 deletion is not compensated by Kv4.2 while SK3 loss is partly compensated by SK2 expression in SNc DA neurons. This study demonstrates that SNc DA neurons are differentially robust to potassium channel deletions, depending on the strength of the compensatory mechanisms engaged. It also provides a general framework for assessing the degree of robustness of electrical phenotype in response to ion channel deletion. RESULTS We first sought to determine whether subtle alterations in motor behavior might have been overlooked in previous studies using the SK3 and Kv4.3 KO mice (Carrasquillo et al, 2012; Jacobsen et al, 2008; Nerbonne et al, 2008). We focused on simple motor tasks known to be modulated by the activity of the nigrostriatal DA pathway, such as spontaneous exploration (Kravitz et al, 2010) and learning of a new motor skill (Beeler et al, 2012; Durieux et al, 2012; Giordano et al, 2018; Yin et al, 2009). In particular, motor learning on the accelerating rotarod is sensitive to DA receptor antagonists and to targeted lesions of the dorsal striatum (Beeler et al, 2012; Durieux et al, 2012; Giordano et al, 2018; Yin et al, 2009). 5 Assessment of motor behavior in SK3 and Kv4.3 KO mice Behaviors of SK3 and Kv4.3 KO mice were compared to wild-type (WT) littermates in order to assess any significant alteration in motor function. Spontaneous locomotor activity was first measured using actimetry chambers, while motor learning abilities were evaluated using the accelerating rotarod test (Figure 1A). SK3 and Kv4.3 KO mice displayed a global level of locomotor activity similar to WT littermates: SK3 KO vs WT, 202.00 ± 18.63, n=12 vs 185.08 ± 19.06, n=12, p=0.532, unpaired t-test; Kv4.3 KO vs WT, 127.69 ± 11.46, n=13 vs 117.40 ± 14.87, n=10; p=0.583, unpaired t-test; Figure 1B). However, the analysis of more specific locomotor features revealed a significant increase in the number of rearing events in SK3 KO mice compared to WT (254.2 ± 31.8, n=12 vs 178.5 ± 15.2, n=12, p=0.043, unpaired t-test)
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