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.

译文

在唐氏综合症 (DS) 的小鼠模型中,过度抑制被认为是认知缺陷 (例如记忆障碍) 的主要原因之一。然而,驱动这种夸张的突触抑制及其行为影响的机制仍不清楚。在这里,我们报告了DS的Ts2Cje小鼠模型中CA1锥体细胞突触抑制的双向改变的存在,这与空间记忆受损有关。此外,我们确定了编码基因Grik1的kainate受体 (KAR) 的三重复制是这些表型的原因。Ts2Cje小鼠中Grik1剂量的正常化可以特异性地恢复空间记忆,并将双向改变逆转为CA1抑制,但没有观察到突触可塑性的变化或其他行为改变。我们建议,由抑制音调干扰而不是广义的过度抑制引起的修改的信息门控是DS中一些特征性认知缺陷的基础。

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