Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl- permeable GABA(A) receptors (GABA(A)Rs) contributes considerably to learning and memory deficits in DS mouse models. However, the efficacy of GABAergic transmission has never been directly assessed in DS. Here GABA(A)R signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABA(A)R-driven Cl- currents (E-Cl) was shifted toward more positive potentials in the hippocampi of adult DS mice. Accordingly, hippocampal expression of the cation Cl-cotransporter NKCC1 was increased in both trisomic mice and individuals with DS. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult DS mice. Our findings demonstrate that GABA is excitatory in adult DS mice and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.