26Identifying dosage sensitive genes is a key to understand the mechanisms 27 underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah 28 DS mouse model (Dp1Yah) show cognitive phenotype and needs to be investigated 29 to identify the main genetic driver. Here, we report that, in the Dp1Yah mice, 3 copies 30 of the Cystathionine-beta-synthase gene (Cbs) are necessary to observe a deficit in 31 the novel object recognition (NOR) paradigm. Moreover, the overexpression of Cbs 32 alone is sufficient to induce NOR deficit. Accordingly targeting the overexpression of 33 human CBS, specifically in Camk2a-expressing neurons, leads to impaired objects 34 discrimination. Altogether this shows that Cbs overdosage is involved in DS learning 35 and memory phenotypes. In order to go further, we identified compounds that interfere 36 with the phenotypical consequence of CBS overdosage in yeast. Pharmacological 37 intervention in the Tg(CBS) with one selected compound restored memory in the novel 38 object recognition. In addition, using a genetic approach, we demonstrated an epistatic 39 interaction between Cbs and Dyrk1a, another human chromosome 21 gene encoding 40 the dual-specificity tyrosine phosphorylation-regulated kinase 1a and an already 41 ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http:/
SIGNIFICANT STATEMENT
50Here, we investigated a region homologous to Hsa21 and located on mouse 51 chromosome 17. We demonstrated using three independent genetic approaches that 52 the overdosage of the Cystathionine-beta-synthase gene (Cbs) gene, encoded in the 53 segment, is necessary and sufficient to induce deficit in novel object recognition (NR). 54In addition, we identified compounds that interfere with the phenotypical 55 consequence of CBS overdosage in yeast and in mouse transgenic lines. Then we 56 analyzed the relation between Cbs overdosage and the consequence of DYRK1a 57 overexpression, a main driver of another region homologous to Hsa21 and we 58 demonstrated that an epistatic interaction exist between Cbs and Dyrk1a affecting 59 different pathways, including synaptic transmission, cell projection morphogenesis, 60 and actin cytoskeleton.