Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of rat synaptosomes of the hippocampus vs. total hippocampus reveals activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites

ABSTRACT: Mammalian target of rapamycin (mTOR) is implicated in synaptic plasticity and local translation in dendrites. Here we found that the mTOR inhibitor, rapamycin, increased the Kv1.1 voltage-gated potassium channel protein in hippocampal neurons and promoted Kv1.1 surface expression on dendrites without altering its axonal expression. Moreover, endogenous Kv1.1 mRNA was detected in dendrites. Using Kv1.1 fused to the photo-convertible fluorescence protein Kaede as a reporter for local synthesis, we observed Kv1.1 synthesis in dendrites upon inhibition of mTOR or the N-methyl-D-aspartate (NMDA) glutamate receptor. Thus, synaptic excitation may cause local suppression of dendritic Kv1 channels by reducing their local synthesis. Experiment Overall Design: mRNA isoloated from the synaptosomes of the hippocampus is compared to mRNA isolated from the total hippocampus to identify mRNAs that are enriched at the synapse

ORGANISM(S): Rattus norvegicus

SUBMITTER: Kimberly Frances Raab-Graham

PROVIDER: E-GEOD-5516 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Many biological processes involve the mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Thus, the challenge of deciphering mTORC1-mediated functions during normal and pathological states in the central nervous system is steep. Because mTORC1 is at the core of translation, we have investigated mTORC1 function in global and regional protein expression. Activation of mTORC1 has been generally regarded to promote translation. Few but recent works have demonstrated that suppression of mTORC1 can promote local protein synthesis. Moreover, excessive mTORC1 activation during disease states represses basal and activity-induced protein synthesis. To determine the role of mTORC1 activation in protein expression, we have used an unbiased, large scale proteomic approach. We provide evidence that a brief repression of mTORC1 activity in vivo by rapamycin has little affect globally, yet leads to a significant remodeling of synaptic proteins, in particular those proteins that reside in the postsynaptic density (PSD). We have also found that curtailing the activity of mTORC1 bidirectionally alters the expression of proteins associated with epilepsy, Alzheimer’s disease, and autism spectrum disorder (ASD)—neurological disorders that exhibit elevated mTORC1 activity. Through a protein-protein interaction network analysis, we have identified common proteins shared among these mTOR-related diseases. One such protein is Parkinson protein 7 (PARK7) which has been implicated in Parkinson’s disease, yet not associated with epilepsy, AD, or ASD. To verify our finding, we provide evidence that the protein expression of PARK7, including new protein synthesis, is sensitive to mTORC1 inhibition. Using cultured neurons from a mouse model of tuberous sclerosis complex (TSC), a disease that displays both epilepsy and ASD phenotypes and has overactive mTOR signaling, we show that PARK7 protein is elevated in the dendrites. Our work offers a comprehensive view of mTORC1 and its role in regulating regional protein expression in normal and diseased states.

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Transcription profiling of rat synaptosomes of the hippocampus vs. total hippocampus reveals activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites

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