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

Abstract

Down syndrome (DS) is the most frequent genetic cause of intellectual disability, and altered GABAergic transmission through Cl-permeable GABAA receptors (GABAARs) 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 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 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.

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Figure 1: CA1 hippocampal pyramidal neurons exhibit excitatory responses to exogenous and endogenous GABA in adult Ts65Dn mice.
Figure 2: Hippocampal CA1 neurons exhibit a less negative ECl in adult Ts65Dn mice than in adult WT mice.
Figure 3: NKCC1 protein expression is increased in the hippocampi of Ts65Dn mice and in samples from human subjects with DS.
Figure 4: Bath application of the FDA-approved NKCC1 inhibitor bumetanide rescues the deficit in hippocampal CA3–CA1 LTP in Ts65Dn mice.
Figure 5: Systemic treatment with bumetanide restores cognitive function in behavioral tasks in Ts65Dn mice.
Figure 6: Effect of bumetanide on memory does not depend on changes in neuronal connectivity.

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Acknowledgements

This work was supported by Compagnia di San Paolo (grant 2008.1267 to L.C.) and the Jerome Lejeune Foundation (grants 995-CA2012A, to A.C., and 1266_CL2014A, to L.C.). Human Down syndrome and control samples were obtained from the Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore. We thank F. Benfenati (Istituto Italiano di Tecnologia (IIT)) for financial support, J. Assad (IIT) for critical reading of the manuscript, M. Pesce (IIT NBT imaging facility) for technical assistance with two-photon microscopy and the staff of the IIT animal facility and genotyping service for their valuable work. We also thank K. Kaila (University of Helsinki, Helsinki, Finland) for providing brain tissue from NKCC1-deficient and KCC2-deficient mice.

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G.D. and S.N. collected and analyzed the electrophysiology data. M.P. collected and analyzed the behavioral data. G.D. prepared the figures. A.C. collected and analyzed the biochemical data. I.F.B. performed animal treatments and collaborated with M.P. on AGS experiments. L.C. and A.C. designed the experiments and wrote the manuscript. All authors read and revised the manuscript.

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Correspondence to Andrea Contestabile or Laura Cancedda.

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A.C. and L.C. are named as co-inventors on International Patent Application PCT/EP2014/078561, filed on December 18, 2014, claiming priority over US Provisional Application US 61/919,195, priority date December 20, 2013.

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Deidda, G., Parrini, M., Naskar, S. et al. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat Med 21, 318–326 (2015). https://doi.org/10.1038/nm.3827

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