Long‐lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5‐selective GABAA inverse agonist


Background and Purpose

Excessive GABAergic inhibition contributes to cognitive dysfunctions in Down syndrome (DS). Selective negative allosteric modulators (NAMs) of α5‐containing GABAA receptors such as α5IA restore learning and memory deficits in Ts65Dn mice modelling DS. This study aimed at testing long‐lasting effects of α5IA on in vivo long‐term potentiation (LTP) and behavior in Ts65Dn mice.

Experimental Approach

We performed in vivo long‐term potentiation (LTP) recordings for six consecutive days in freely moving Ts65Dn mice and their wild‐type littermates, treated with vehicle or α5IA. In parallel, Ts65Dn mice were subjected to various learning and memory tests (Y‐maze, Morris water maze or the novel object recognition) up to seven days following one single injection of α5IA or vehicle.

Key Results

We found that LTP could not be evoked in vivo in Ts65Dn mice at the hippocampal CA3‐CA1 synapse. However, this deficit was sustainably reversed for at least six consecutive days following a single injection of α5IA. This long‐lasting effect of α5IA was also unveiled when assessing working and long‐term memory deficits in Ts65Dn mice.

Conclusion and Implications

We show for the first time in vivo LTP deficits in Ts65Dn mice. These deficits are restored for at least six days following acute treatment with α5IA and might be the substrate for the long‐lasting pharmacological effects of α5IA demonstrated here on spatial working and long‐term recognition and spatial memory tasks. Altogether, these results highlight the interest of NAMs of α5‐containing GABAA receptors for treating cognitive deficits associated with DS.


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