Abstract: Trisomy 21 or Down syndrome (DS) is the most
common cause of intellectual disability of a genetic origin.
The Ts65Dn (TS) mouse, which is the most commonly used
and best-characterized mouse model of DS, displays many of
the cognitive, neuromorphological, and biochemical anomalies
that are found in the human condition. One of the mechanisms
that have been proposed to be responsible for the cognitive
deficits in this mouse model is impaired GABAmediated
inhibition. Because of the well-known modulatory
role of GABAA ?5 subunit-containing receptors in cognitive
processes, these receptors are considered to be potential targets
for improving the intellectual disability in DS. The chronic
administration of GABAA ?5-negative allosteric modulators
has been shown to be procognitive without anxiogenic or
proconvulsant side effects. In the present study, we use a genetic
approach to evaluate the contribution of GABAA ?5
subunit-containing receptors to the cognitive, electrophysiological,
and neuromorphological deficits in TS mice.We show
that reducing the expression of GABAA ?5 receptors by deleting
one or two copies of the Gabra5 gene in TS mice partially
ameliorated the cognitive impairments, improved longterm
potentiation, enhanced neural differentiation and maturation,
and normalized the density of the GABAergic synapse
markers. Reducing the gene dosage of Gabra5 in TS mice did
not induce motor alterations and anxiety or affect the viability
of the mice. Our results provide further evidence of the role of
GABAA ?5 receptor-mediated inhibition in cognitive impairment
in the TS mouse model of DS.
