Altered GABAergic transmission through Cl^–-permeable GABA_A receptors (GABA_ARs) is known to contribute to learning and memory deficits in Down syndrome mouse models. In this study, GABA_AR signaling was found to be excitatory rather than inhibitory, and the reversal potential for GABA_AR-driven Cl^– currents (E_Cl) 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 E_Cl, 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.

http://www.nature.com/nm/journal/v21/n4/abs/nm.3827.html

Posted by Nicola Brunetti-Pierri