Neuromodulation in the central nervous system : from hippocampus to spinal cord

Dans ce travail, nous avons étudié, dans un premier temps, la modulation par tachykinines de la transmission synaptique inhibitrice dans l'hippocampe. Dans un deuxième temps, nous avons examiné l'effet de la vasopressine sur les motoneurones de la moelle lombaire et sur les motoneurones honteux. Dans un troisième temps, nous avons mis en évidence la présence de récepteurs nicotiniques fonctionnels sur les motoneurones de la moelle épinière lombaire. Enfin, nous avons participé à la caractérisation d'un nouveau modulateur allostérique du récepteur nicotinique de type α7 ainsi qu'à la démonstration que ces récepteurs sont régulés de façon négative par la phosphorylation des tyrosines et par les kinases de la famille Src

Action des tachykinines dans l'hippocampe : facilitation de l'activité synaptique inhibitrice dans les cellules principales et les interneurones GABAergiques

Afin d'apporter la preuve directe que les interneurones répondant aux tachykinines peuvent établir des connections monosynaptiques avec les cellules pyramidales, nous avons réalisé des enregistrements simultanés de paires d'interneurones/cellules pyramidales. Dans les paires connectées, le peptide provoquait une décharge de potentiels d'action dans l'interneurone et, de façon concomitante, engendrait une augmentation des CPSIs dans la cellule pyramidale. Dans les paires non connectées, nous n'avons pas mis en évidence, en présence du peptide, une activation de synapses inhibitrices "silencieuses". Nous avons aussi démontré que l'activation d'interneurones par les tachykinines pouvait indirectement inhiber d'autres interneurones. Nous avons pu montrer que cet effet était dû à des récepteurs de type NK1. Nous concluons que les tachykinines peuvent influencer le fonctionnement de l'hippocampe en inhibant indirectement les cellules pyramidales mais aussi d'autres interneurones inhibiteurs. Selon la balance précise entre ces effets, les tachykinines peuvent promouvoir soit l'activation, soit la dépression de l'hippocampe

Identified motoneurons involved in sexual and eliminative functions in the rat are powerfully excited by vasopressin and tachykinins

The pudendal motor system is constituted by striated muscles of the pelvic floor and the spinal motoneurons that innervate them. It plays a role in eliminative functions of the bladder and intestine and in sexual function. Pudendal motoneurons are located in the ventral horn of the caudal lumbar spinal cord and send their axon into the pudendal nerve. In the rat, binding sites for vasopressin and tachykinin are present in the dorsomedial and dorsolateral pudendal nuclei, suggesting that these neuropeptides may affect pudendal motoneurons. The aim of the present study was to investigate possible effects of vasopressin and tachykinins on these motoneurons. Recordings were performed in spinal cord slices of young male rats using the whole-cell patch-clamp technique. Before recording, motoneurons were identified by 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine, 4-chlorobenzenesulfonate retrograde labeling. The identification was confirmed, a posteriori, by choline acetyltransferase immunocytochemistry. Vasopressin and tachykinins caused a powerful excitation of pudendal motoneurons. The peptide-evoked depolarization, or the peptide-evoked inward current, persisted in the presence of tetrodotoxin, indicating that these effects were mainly postsynaptic. By using selective receptor agonists and antagonist, we determined that vasopressin acted via vasopressin 1a (V1a), but not V1b, V2, or oxytocin receptors, whereas tachykinins acted via neurokinin 1 (NK1), but not NK2 or NK3, receptors. Vasopressin acted by enhancing a nonselective cationic conductance; in some motoneurons, it also probably suppressed a resting K+ conductance. Our data show that vasopressin and tachykinins can excite pudendal motoneurons and thus influence the force of striated perineal muscles involved in eliminative and sexual functions

A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization

Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders