Alterations in excitatory-inhibitory balance occur in Down syndrome and could be responsible for cognitive
deficits observed through the life of all individuals carrying an extra copy of chromosome 21. Excess of inhibition in the
adult could produce synaptic plasticity deficits that may be a primary mechanism contributing to learning and memory
impairments. In this study we discuss pharmacological treatments that could potentially alleviate neuronal inhibition and
have been tested in a mouse model of Down syndrome. γ-aminobutyric acid (GABA) is the major inhibitory
neurotransmitter in the mature central nervous system that binds to GABA-benzodiazepine receptors, opens a chloride
channel and reduces neuronal excitability. These receptors have been extensively studied as targets for treatment of
epilepsy, anxiety, sleep, cognitive disorders and the induction of sedation. Molecules that are either antagonists or inverse
agonists of the GABA-benzodiazepine receptors are able to reduce inhibitory GABAergic transmission. However
modulating the excitatory-inhibitory balance towards increase of cognition without inducing seizures remains difficult
particularly when using GABA antagonists. In this study we review data from the literature obtained using inverse
agonists selective for the α5-subunit containing receptor. Such inverse agonists, initially developed as cognitive enhancers
for treatment of memory impairments, proved to be very efficient in reversing learning and memory deficits in a Down
syndrome mouse model after acute treatment.
Keywords: Chloride, cognitive enhancer, down syndrome, GABA, immediate early genes, inhibition.
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