Control of contextual memory through interneuronal α5-GABA_Areceptors

Abstract

Abstractγ-aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and they are strongly implicated in the control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that selective elimination of α5-GABAARs from either interneurons or pyramidal cells prevented the general anesthetic etomidate from suppressing contextual learning. Using Ca2+ imaging of hippocampal neuronal activity in freely exploring mice, we also found that etomidate interfered with the development of place cells and spatial engrams in wild type mice but not in interneuron-specific α5-GABAAR knockout mice. These findings show that α5-GABAARs on interneurons as well as pyramidal neurons mediate etomidate-induced amnesia.

Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP

“…As we also observed previously (Zhu et al, 2022), approximately one-half of cells that fired during session 1 also fired during session 2 (Fig. 3B).…”

“…Since our present results appear to rule out the possibility that a greater sensitivity of other brain structures can account for the mismatch, this leaves the actions of (R)-CPP on GluN2A-expressing interneurons as the most likely explanation (Zhu et al, 2022). GABAergic interneurons are key to maintaining the balance of synaptic inhibition and excitation within hippocampal memory-encoding circuits, and they themselves display diverse and subtypespecific expression of NMDARs (Booker et al, 2021;Huntley et al, 2020;Perszyk et al, 2016).…”

“…Like place cells, spatial engrams, as quantified by RMcorr and PVcorr (Zhu et al, 2022), are also defined by spatial modulation of firing rates. However, spatial engrams as defined in this manner include all cells that are active in both environments, not just place cells, because both have been shown to code for meaningful spatial information (Sheintuch et al, 2020;Stefanini et al, 2020;Tanaka et al, 2018).…”

Changes in Memory, Sedation, and Receptor Kinetics Imparted by the β2-N265M and β3-N265M GABAA Receptor Point Mutations

“…In addition, β3 subunits are more heavily expressed by pyramidal neurons, whereas β2 subunits are concentrated in interneurons [ 45 ]. Interestingly, the elimination of α5-GABA A Rs from either pyramidal neurons or interneurons interferes with suppression of memory by low doses of etomidate [ 47 ], just as the N265M mutation of either β2- or β3-GABA A Rs interferes with memory formation under drug-free conditions. Thus, the intrinsic characteristics of both β2- and β3-GABA A Rs appear to be optimally tuned to support mnemonic function, and altering their activity by pharmacologic or genetic manipulations causes memory to fail.…”

Avaliação da influência do ciclo estral e os efeitos da inibição da recaptação de serotonina e noradrenalina e da inibição da síntese de corticosterona nas respostas ao modelo de medo condicionado ao contexto

“…A diminuição nos níveis de P4 parecem estar relacionadas ao aumento de comportamentos do tipo ansiosos e dos níveis de CORT no LCE(ISLAS-PRECIADO et al, 2022). Além disso, os receptores GABA-A estão envolvidos no aprendizado espacial da memória contextual(ZHU et al, 2023). Da mesma forma, a literatura vem apontando para a participação da ALO em transtornos psiquiátricos, sendo encontrada emníveis reduzidos em situações de estresse crônico e ansiedade (BALI; JAGGI, 2014; SCHÜLE; NOTHDURFTER; RUPPRECHT, 2014).…”