Instituto de Neurociencias CSIC-UMH, 03550, San Juan de Alicante, Spain.
LNC Therapeutics, 33000, Bordeaux, France.
Nat Commun. 2019 Nov 1;10(1):4991. doi: 10.1038/s41467-019-13004-9.
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.
过度抑制被认为是唐氏综合征（DS）小鼠模型认知缺陷（例如记忆障碍）的主要原因之一。然而，导致这种过度突触抑制及其行为影响的机制仍不清楚。在这里，我们报告了在 Ts2Cje 唐氏综合征小鼠模型中 CA1 锥体神经元的突触抑制存在双向改变，这与空间记忆受损有关。此外，我们发现编码 kainate 受体 (KAR) 的基因 Grik1 的三倍体是这些表型的原因。在 Ts2Cje 小鼠中特异性地使 Grik1 剂量正常化，恢复了空间记忆并逆转了 CA1 抑制的双向改变，但没有改变突触可塑性或观察到的其他行为改变。我们提出，由抑制性音调紊乱引起的信息门控改变而不是普遍的过度抑制，是 DS 中一些特征性认知缺陷的基础。
