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

• Published in: Nature medicine Vol. 21; no. 4; pp. 318 - 326
• Main Authors: Deidda, Gabriele, Parrini, Martina, Naskar, Shovan, Bozarth, Ignacio F, Contestabile, Andrea, Cancedda, Laura
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2015; Nature Publishing Group
• Subjects: 14; 14/19; 631/378/1689/2608; 64/110; 692/699/375/366; 9/30; 9/74; 96/1; 96/35; Adolescent; Adult; Animal memory; Animals; Behavior, Animal; Biomedicine; Brain; Bumetanide - chemistry; Cancer Research; Crosses, Genetic; Disabilities; Disease Models, Animal; Down syndrome; Down Syndrome - metabolism; Female; Hippocampus - metabolism; Humans; Infectious Diseases; Male; Memory - physiology; Metabolic Diseases; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Molecular Medicine; Neurobiology; Neuronal Plasticity; Neurons - metabolism; Neurosciences; Patch-Clamp Techniques; Plasticity; Receptors, GABA-A - metabolism; Rodents; Signal Transduction; Time Factors; Young Adult
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3827

Both chronic and acute treatment of adult Ts65Dn mice with the FDA-approved NKCC1 inhibitor bumetanide suppressed aberrant excitatory GABA A R signaling and rescued synaptic plasticity deficits and cognitive disabilities in this 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 E Cl , 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.