Network interactions of medial prefrontal cortex, hippocampus and reuniens nucleus of the midline thalamus

Le présent mémoire corrobore l'hypothèse selon laquelle l'hippocampe, le cortex préfrontal et le noyau reuniens du thalamus constituent un réseau fonctionnel dans lequel le noyau reuniens servirait d'interfacé entre l'hippocampe et le cortex pré frontal. Bien que la voie hippocampo-corticale de ce réseau ait été abondamment étudiée, cela n'est pas le cas pour la voie reuniens-préfrontale. Nous décrivons ici, pour la première fois, la réponse de neurones du cortex préfrontal médian aux stimulations du noyau reuniens. Chez des chats sous anesthésie (kétamine-xylazine), nous avons effectué simulatanément 1) des enregistrements intra- et extracellulaires dans le cortex préfrontal médian et 2) des stimulations du noyau reuniens ou de l'hippocampe à l'aide d'électrodes bipolaires. Nous avons ainsi démontré que la réponse de neurones du cortex préfrontal médian aux stimulations du noyau reuniens est distincte des réponses évoquées par des stimulations hippocampiques, que la voie reuniens-préfrontale est sujette à la plasticité à court terme et qu'une région restreinte du cortex préfrontal médian sert de relai à la voie hippocampo-cortico-thalamique

Enhanced prefrontal serotonin 5-HT1A currents in a mouse model of Williams-Beuren syndrome with low innate anxiety

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1+/−) or homozygously (Gtf2ird1−/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1−/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1−/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1−/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1−/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines