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Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model.

Sergio Valbuena, Álvaro García, Wilfrid Mazier, Ana V. Paternain & Juan Lerma

Nature Communications, 10, Article number: 4991
Available 1 Nov 2019
Doi link: https://doi.org/10.1038/s41467-019-13004-9

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Why people with Down syndrome have spatial memory problems? Spanish researchers have the answer.
• The triplication of a single gene, GRIK1, located on chromosome 21, causes alterations in inhibitory synaptic transmission in the hippocampus, related to memory and space orientation.
• By normalizing the extra dose of GRIK1 in a transgenic mouse model, spatial memory problems disappear.
• The finding, carried out by scientists from the UMH-CSIC Institute of Neurosciences in Alicante (Spain), is published in the journal Nature Communications.

Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS.

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