Abstract
BackgroundMutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown.MethodsWe utilized Tsc2+/− mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2+/− and following mGluR-LTD synaptic plasticity.ResultsRibosome profiling reveals that in Tsc2+/− mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1−/y hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice.ConclusionThese results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/− mice.
Highlights
Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability
Translational profiling of the TSC hippocampus The GTPase activating protein tuberous sclerosis complex (TSC) is an upstream but indirect repressor of mechanistic target of rapamycin (mTOR), a kinase which forms the multi-subunit complex mTORC1 to stimulate translation in response to a number of signaling inputs including activated group I metabotropic glutamate receptors. mGluR5 activation leads to long-term depression (LTD), a protein synthesis-dependent form of synaptic plasticity frequently examined at hippocampal Schafer collateralCA1 synapses (Fig. 1a) [12]
TSC is a neurodevelopmental disorder characterized by autism, epilepsy, and intellectual disability, and to study the role of TSC2 in synaptic plasticity, we generated mice lacking one copy of the Tsc2 gene, which will be referred to as the Tsc2+/− mouse
Summary
Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by benign tumor growth in multiple organs and neuropsychiatric symptoms. Rheb activates the mechanistic target of rapamycin (mTOR), a kinase that forms two biochemically distinct complexes: mTORC1 and mTORC2 [6]. Complete loss of TSC1 or TSC2 leads to excessive mTOR activity, and mutations in other components of the mTOR pathway are linked to autism in humans such as PTEN, RHEB, and MTOR [10, 11]. Pharmacological options are available for the treatment for seizures in individuals with TSC, there currently is no effective pharmacological treatment for the neuropsychiatric symptoms of intellectual disability and autism
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