Investigative Studies into mTORC1-Dependent Dendritic Branch Potentiation in TSC
Abstract
Many patients with TSC have long-term memory impairment. Yet, the underlying mechanism leading to cognitive deficits is not well understood. Memories are stored at clusters of synapses, within a dendritic branch, and requires the protein composition of that branch to be remodeled to strengthen communication. In the proposed studies, we will specifically test the hypothesis that in preclinical models of TSC branch potentiation is reduced. Indeed, calcium imaging of neurons isolated from WT, TSC1 KO, and TSC1 heterozyotic (Het) mice reveals a dose-dependent loss of branch potentiation. We are investigating the underlying molecular mechanism leading to deficits in branch-specific potentiation in TSC. We found that several mRNAs that code for ion channels are predicted to be regulated by the microRNA miR-129-5p. These ion channels are overexpressed and mislocalized in TSC null dendrites and include Kv1.1, CaV2.2, and alpha2delta1. Unexpectedly, blocking N-type calcium channels (CaV2.2) with its specific antagonist -conotoxin restores branch-specific potentiation in TSC1 null neurons. Together these studies are the first to show that TSC neurons lack branch-specific potentiation and an underlying mechanism, a form of information storage that may underlie memory. Over the next year we will further characterize miR-129-5p expression pattern and its role in ion channel expression underlying branch potentiation. Note: Covid-19 caused our lab to shut down, reduce our mouse colony size, and has slowed down the supply chain thus, limiting our research.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2021
- Accession Number
- AD1145729
Entities
People
- Kimberly F Raab-Graham
Organizations
- Wake Forest University