Altered GABAergic transmission through Cl–-permeable GABAA receptors (GABAARs) is known to contribute to learning and memory deficits in Down syndrome mouse models. In this study, GABAAR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABAAR-driven Cl– currents (ECl) was shifted toward more positive potentials in the hippocampi of adult Down syndrome mice. Hippocampal expression of cation Cl– cotransporter NKCC1 was increased in both trisomic mice and individuals with Down syndrome. Notably, NKCC1 inhibition by the FDA-approved drug bumetanide restored ECl, synaptic plasticity and hippocampus-dependent memory in adult Down syndrome mice. Therefore, this paper identifies the excitatory role of GABA in Down syndrome brain and suggests a new approach for therapy of cognitive disabilities in Down syndrome.
Posted by Nicola Brunetti-Pierri