Editors' ChoiceNeuroscience

Excited by GABA

Sci. Signal.  12 May 2015:
Vol. 8, Issue 376, pp. ec121
DOI: 10.1126/scisignal.aac5311

The neurotransmitter γ-aminobutyric acid (GABA) inhibits neuronal activity in the adult brain. Upon ligand activation, GABAA receptors (GABAARs) allow Cl ions to flow into the cell, thereby hypolarizing the cell and inhibiting action potentials. Deidda et al. found that GABA was excitatory rather than inhibitory in adult Ts65Dn mice. Ts65Dn mice exhibit cognitive impairments similar to humans with Down syndrome due to duplication of a portion of the mouse chromosome that is syntenic to one arm of human chromosome 21, trisomy of which causes Down syndrome. As expected, application of GABA reduced the frequency of action potentials in hippocampal slices from wild-type (WT) adult mice. However, GABA treatment increased the frequency of action potentials in hippocampal slices from Ts65Dn mice in a GABAAR-dependent manner because the cells in these slices had an increased resting intracellular Cl concentration. Compared with controls, the abundance of the Cl importer NKCC1 was increased in hippocampal extracts from Ts65Dn mice and from human Down syndrome samples obtained postmortem. Application of the NKCC1 inhibitor bumetanide reduced both spontaneous and GABA-induced firing and rescued long-term potentiation and synaptic plasticity in hippocampal slices from Ts65Dn mice. Intraperitoneal injections of bumetanide improved the performance of adult Ts65Dn mice in various behavioral tests that measure hippocampal-dependent cognitive function. Perturbations of GABAergic neural circuits are associated with seizures, and both Down syndrome patients and Ts65Dn mice have increased susceptibility to seizures. Although bumetanide did not reverse the susceptibility of Ts65Dn mice to audiogenic seizures, it did not increase seizure susceptibility, suggesting that bumetanide may not increase seizure risk in Down syndrome patients. Bumetanide is FDA-approved for use as a diuretic, which may facilitate the design of clinical trials to assess this drug's potential to benefit Down syndrome patients (see commentary by Costa).

G. Deidda, M. Parrini, S. Naskar, I. F Bozarth, A. Contestabile, L. Cancedda, Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat. Med. 21, 318–326 (2015). [PubMed]

A. C. Costa, Intracellular chloride accumulation: A possible mechanism for cognitive deficits in Down syndrome. Nat. Med. 21, 312–313 (2015). [PubMed]

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