Biology subjects

Seutin, V.

Publications and source records attributed to Seutin, V..

4 recordsLinked to original sources

bioRxiv2025

A fast and tiny current as common generator of slow regular pacemaking in brain and heart

Slow pacemaking is a key physiological process in specific excitable cells, yet its underlying mechanism remains debated. Here we identify a conserved, voltage-dependent pacemaker current that is essential for slow, regular firing in both midbrain dopaminergic neurons and sinoatrial node myocytes. Conductance-based models incorporating this current reproduce stable pacemaking, requiring a fast-activating, small-amplitude current. This is further confirmed by dynamic-clamp experiments in dopaminergic neurons. Replacing the pacemaker current in a model with a voltage-independent conductance such as the non-selective sodium leak channels fails to sustain slow rhythmicity, highlighting the necessity for an adequate voltage dependence. Our results suggest a novel and shared biophysical mechanism for slow pacemaking in neuronal and cardiac systems.

physiology↗

bioRxiv2024

Co-agonist glycine controls the occurrence of bursts by activating extrasynaptic NMDARs in nigral dopamine neurons

NMDA receptor activation in pars compacta substantia nigra dopamine neurons is central to the generation of bursting activity, a key signal temporally associated to movement initiation. The site of the NMDAR pool (synaptic and/or extrasynaptic) as well as the identity of the co-agonist involved in the ignition of this phasic activity remains unknown. Using ex vivo electrophysiological recordings, we demonstrate that NMDARs located outside synapses are preponderant for this firing. This pool of receptors is recruited during intense synaptic activity via spillover of glutamate and require the binding of NMDAR co-agonist glycine for their full activation. Synaptic NMDARs are not directly involved in bursting and are activated by D-serine, a distinct co-agonist. Location dependency of NMDARs and co-agonist underlying burst generation may serve as a guideline in understanding the physiological role of dopamine neurons in health and disease. TeaserExtrasynaptic NMDARs recruited by spillover and glycine allow the generation of bursts in dopamine neurons.

neuroscience↗

bioRxiv2020

An unconventional conductance is required for pacemaking of nigral dopamine neurons

Although several ionic mechanisms are known to control rate and regularity of the pacemaker in dopamine (DA) neurons from the substantia nigra pars compacta (SNc), a conductance essential for pacing has yet to be defined. Here we provide pharmacological evidence that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidine (XG), an established blocker of gating pore currents in mutant voltage gated sodium channels, selectively stops pacemaking of DA SNc neurons and is without effect on the main pore of their voltage-gated channels. We isolated a voltage-dependent, non-inactivating XG-sensitive current of 20-25 pA which operates in the relevant subthreshold range and is carried by both Na+ and Cl- ions. While the molecular identity of this conductance remains to be determined, we show that this XG-sensitive current is crucial to sustain pacemaking in these neurons.

neuroscience↗

bioRxiv2020

Ketamine selectively enhances AMPA neurotransmission onto a subgroup of identified serotoninergic neurons of the rat dorsal raphe

Although the fast antidepressant effect of ketamine is now well established clinically, neither its mechanism(s) nor its main site(s) of action is clearly defined. Because enhanced serotoninergic (5-HT) transmission is an important part of the antidepressant effect of various drug classes, we asked whether ketamine and one of its metabolites (hydroxynorketamine [HNK]), both used in their racemic form, may modulate the excitatory drive onto these neurons. Using whole-cell recordings from pharmacologically identified 5-HT and non-5-HT neurons in juvenile rat dorsal raphe slices, we found that both ketamine and HNK (10 {micro}M) increase excitatory AMPA neurotransmission onto a subset (50%) of 5-HT neurons, whereas other 5-HT cells were unaffected. Both compounds increased the amplitude as well as the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) mediated by AMPA receptors. The effect of ketamine was more robust than the one of HNK, since it significantly enhanced the charge transfer through AMPA channels, whereas HNK did not. The increase in the excitatory drive induced by ketamine was dependent on NMDA receptor blockade. In the presence of tetrodotoxin, the effect of ketamine was markedly reduced. Non-5-HT neurons, on the other hand, were unaffected by the drugs. We conclude that ketamine and HNK increase the excitatory drive onto a subset of 5-HT neurons by promoting glutamate release and possibly also through a postsynaptic action. The effect of ketamine is dependent on NMDA receptor modulation and appears to involve a network effect. These findings improve our understanding of the fast-acting antidepressant effect of ketamine. SIGNIFICANCE STATEMENTThe mechanisms of ketamines antidepressant effect are currently controversial. We asked whether the drug would produce changes is the strength of synaptic inputs onto serotoninergic neurons of the dorsal raphe. We found that this is indeed the case in about half of these neurons. The action of ketamine was mimicked to some extent by its well-known metabolite hydroxynorketamine, was dependent on NMDA receptor activation and probably involved a local network effect. It remains to be determined if the differential susceptibility of serotoninergic neurons to the drug correlates with any differential inputs and/or outputs.

neuroscience↗