Prenatal treatment with rapamycin restores enhanced hippocampal mGluR‑LTD and mushroom spine size in a Down’s syndrome mouse model

Abstract

Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory defcits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactiva‑ tion, and related plasticity as well as memory defcits in Ts1Cje mice, a DS experimental model. Here we character‑ ize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological efect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability