Morpho-functional properties of early-born GABAergic neurons in developing and adult CA1 hippocampal circuits

Les neurones GABAergiques sont une composante majeure des réseaux neuronaux corticaux. Au cours du développement, les neurones GABAergiques pionniers générés aux stades les plus précoces de l’embryogénèse forment une sous-population de neurones « hubs ». Cependant, leurs propriétés et leurs fonctions à l'âge adulte restent inconnus. En combinant différentes techniques, nous montrons que ces neurones pionniers ont également une fonction « hub » dans la région CA1 en développement in vitro et qu’ils maintiennent une forte connectivité fonctionnelle pendant les périodes de veille calme chez la souris adulte in vivo. Ces neurones, peu actifs de façon spontanée chez l’adulte, sont préférentiellement recrutés pendant les activités calciques synchrones souvent associées aux oscillations de type « SWRs ». Ceci est compatible avec leur faible excitabilité intrinsèque, révélée par des enregistrements en courant-imposé. L’étude des connexions synaptiques afférentes des neurones pionniers de CA1 adulte, par optogénétique, révèle un schéma de connectivité remarquable avec des entrées synaptiques GABAergiques issues du septum et la quasi-absence d’entrées thalamiques. Localement, ces neurones reçoivent moins de courants postsynaptiques GABAergiques, témoignant d’une intégration différentielle dans le réseau GABAergique inhibiteur. Enfin, nous montrons qu’une majorité significative de ces neurones pionniers appartiennent à la famille des neurones à projection longue distance. En conclusion, nous montrons que les neurones GABAergiques pionniers sont prédéterminés à occuper une place remarquable dans l’organisation fonctionnelle et structurale de l’hippocampe tout au long de leur vie.The remarkable diversity of cortical GABAergic neurons is rooted, at least in part, in their embryonic origins. Adding to the spatial control of interneuron specification is a temporal schedule that has significant impact on their fate. In the CA3 region of the hippocampus, GABAergic cells born the earliest (ebGABA) form a sparse subpopulation acting as ‘hubs’ during development and surviving until adulthood. However, their properties and function in adulthood remain elusive. Using a combination of techniques, we demonstrate that ebGABA neurons also operate as “hubs” in the developing CA1 region in vitro and that they seem to maintain such remarkable functional connectivity into adulthood as observed during quiet rest in vivo. EbGABA display a lower spontaneous activity rate, as expected from their lower intrinsic excitability and are preferentially recruited during the synchronous calcium events previously shown to be associated with SWRs. EbGABA also display a remarkable synaptic connectivity scheme as they receive long-range GABAergic septal inputs but are almost excluded from thalamic afferents. Locally, they receive fewer spontaneous inhibitory postsynaptic currents, indicating a particular integration into local GABAergic circuits. Moreover, using combinatorial immunohistochemistry, we have shown that a majority of these ebGABA neurons are long-range projection GABAergic neurons. We conclude that, ebGABA cells are predetermined to become exceptional nodes in the functional and structural organization of the hippocampus, throughout their lifetime

Hippocampal hub neurons maintain distinct connectivity throughout their lifetime

International audienceThe temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as 'hubs' by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during loco-motion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions