The lncRNA Snhg11 is required for synaptic function, neurogenesis and memory and is downregulated in the dentate gyrus of Down syndrome mouse models

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability. Even though advances in the last decades have allowed better delineation of its pathogenetic mechanisms, its cellular and molecular bases are still poorly understood. Here, single-nuclei transcriptional profiles of the hippocampus of a DS mouse model revealed that the trisomy results in a highly cell-type specific alteration of the transcriptome. Strikingly, we observe a major transcriptomic shift in trisomic granule cells from the dentate gyrus (DG), without important changes in other hippocampal regions. We identified the small nucleolar RNA host gene 11, Snhg11, specifically downregulated in the trisomic DG, as the main contributor to the observed shift. Knockdown of Snhg11 in the DG of wild-type mice impairs synaptic function and adult neurogenesis and recapitulates trisomic hippocampal-dependent cognitive phenotypes. Our work highlights the importance of this long non-coding RNA in intellectual disability and reveals its functional involvement in the DG. These findings suggest the DG as a main region for the memory deficits observed in DS and indicate the relevance of new players such as long non-coding RNAs in its etiology.

Defective engram allocation contributes to impaired fear memory performance in Down syndrome

“…A sparser neuronal ensemble activation was also detected in a previous study in the CA1 region of Ts65Dn, upon exposure to novel environments [24]. In addition, a recent study from our laboratory found a lack of upregulation of Arc levels immediately after learning in Ts65Dn mice while Arc levels did not differ in basal conditions [25]. It might be possible that cell-autonomous mechanisms, such as impaired intrinsic excitability [39,40,45] or non-autonomous factors might lower the number of active neurons in response to learning cues.…”

“…Cognitive deficits have been extensively described in Ts65Dn mice, especially deficits in hippocampal-dependent tasks such as NORT [25,32] and CFC [15,33]. During the training session, Ts65Dn mice showed normal performance along the training session, with a significant increase of freezing during the training session to levels similar to the WT (ANOVA repeated measures; F(3,18) = 0.88; genotype effect N.S.…”

“…Decreased neuronal activation was reported in the CA1 region of Ts65Dn during the exploration of novel environments [24]. Similarly, a reduction of Arc expression in the hippocampus after a novel object recognition test (NORT) was recently described in trisomic mice, compared to wild type (WT) littermates [25]. Altogether, this body of mounting evidence supports that engrams are probably defective in DS.…”