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Intracellular chloride accumulation: a possible mechanism for cognitive deficits in Down syndrome

Nature Medicine volume 21, pages 312–313 (2015)Cite this article

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A study involving a mouse model of Down syndrome and analysis of human postmortem brain samples indicates that hippocampal GABAA receptor signaling in Down syndrome may be excitatory. This advance promises new clinical applications in Down syndrome.

Down syndrome (DS) is the phenotypic consequence of an extranumerary chromosome 21 (trisomy 21) (ref. 1,2). DS affects approximately 1 in 700 live births, and it has a prevalence of approximately 1 in 1,000 in the general population3. Persons with this genetic disorder typically have a moderate degree of intellectual disability, although there is a wide range of cognitive functioning among individuals. This neurodevelopmental disability is typically global, although disproportionate deficits in hippocampus- and prefrontal cortex-dependent functions have been well documented4. A neuropathology indistinguishable from Alzheimer disease inevitably develops as a person with DS ages into the mid-thirties to early forties, which probably leads to the high prevalence of early-onset dementia in the fifth or sixth decade of life5. Trisomy 21 also affects the central nervous system (CNS) in a variety of additional ways, including causing an increased incidence of seizure disorder in relation to the general population.

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Figure 1: Schematic model of GABAA receptor–mediated neurotransmission in a mouse model of DS.

Kim Caesar/Nature Publishing Group

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  1. Alberto C. Costa is in the Department of Pediatrics, Division of Pediatric Neurology, Case Western Reserve University, Cleveland, Ohio, USA.,

    Alberto C Costa

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  1. Alberto C Costa
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Correspondence to Alberto C Costa.

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Costa, A. Intracellular chloride accumulation: a possible mechanism for cognitive deficits in Down syndrome. Nat Med 21, 312–313 (2015). https://doi.org/10.1038/nm.3836

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