Impaired mTOR-Macroautophagy and Neurocognitive Deficits in Tuberous Sclerosis Complex
Abstract
This study is designed to identify mTOR-downstream molecules or pathways that account for synaptic and cognitive deficits in TSC, with the goal of identifying targets for more specific treatment. We had focused on macroautophagy (autophagy hereafter), a homeostatic catabolic degradation process down stream of mTOR, which is inhibited by hyperactive mTOR in Tsc1/2 deficient mouse brain. During the first project year, we had found significant cognitive impairment in Tsc2 /- mice and Atg7CKO autophagy deficient mice at the age of 3months. These mice however did not show cognitive deficits at 1month of age. Prior to the occurrence of cognitive impairment, Atg7CKO mice exhibited an increase in NMDA:AMPA ratio, increased frequency of miniature EPSCs and increased dendritic spine density, all indicating a blockade in postnatal synapse maturation. Atg7CKO mice moreover showed impaired CA3-CA1 long-term potentiation (LTP) and long term depression (LTD), both of which are well-known electrophysiological surrogates of hippocampus dependent learning and memory. Our findings therefore suggest that Autophagy is essential for synapse maturation and the development of normal synaptic plasticity and cognitive functions. We will continue to examine whether autophagy deficiency may underlie cognitive impairment in Tsc1/2 mutant mice during the next reporting period.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2018
- Accession Number
- AD1063846
Entities
People
- Guomei Tang