Abstract
Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize 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 effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.
Highlights
Down syndrome (DS), known as trisomy 21, is one of the most common causes of intellectual disability
We found that the Brain Derived Neurotrophic Factor (BDNF)-dependent Long-Term Potentiation (LTP) is abolished in the Ts1Cje hippocampus, and that the specific Mammalian target of rapamycin (mTOR) inhibitor rapamycin fully restored this type of plasticity [7]
Proteomic analysis of hippocampal SNs from Ts1Cje mice In a previous work we found that Ts1Cje mice showed impaired BDNF-LTP, which was restored by the mTOR inhibitor rapamycin [7]
Summary
DS, known as trisomy 21, is one of the most common causes of intellectual disability. We have previously shown that synaptic local translation, a key process for plasticity and hippocampal-dependent memory, is deregulated in the DS mouse model Ts1Cje [2] due to mTOR hyperactivation [3]. MTOR hyperactivation has been found in subjects with DS [4, 5]. In Ts1Cje mice, mTOR hyperactivation seems to be caused by increased levels of Brain Derived Neurotrophic Factor (BDNF) that saturate the BDNF–TrkB–Akt–mTOR. The mTOR pathway is known to participate in other forms of plasticity, such as mGluR-LTD. This is mediated by group I metabotropic glutamate receptors and relies on protein translation [8]. MTORC1 is mainly involved in translational control, mitochondrial function and autophagy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
