Accession Number:

AD1087454

Title:

Impaired mTOR Macroautophagy and Neurocognitive Deficits in Tuberous Sclerosis Complex

Descriptive Note:

Technical Report,15 Jun 2018,14 Jun 2019

Corporate Author:

Columbia University Medical Center New York United States

Personal Author(s):

Report Date:

2019-07-01

Pagination or Media Count:

17.0

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 downstream of mTOR, which is inhibited by hyperactive mTOR in Tsc12 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 3 months. These mice however did not show cognitive deficits at 1 month of age. Prior to the occurrence of cognitive impairment, Atg7CKO mice exhibited an increase in NMDAAMPA 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 Tsc12 mutant mice during the next reporting period.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE