Long-term activity-induced changes in the brain : a study of translational regulation and structural plasticity

Long-lasting changes must take place in the brain to store the skills and memories that have been learned by the organism throughout its history. Long-term memory (LTM), and its cellular correlate, the late-phase of long-term potentiation (L-LTP), require protein synthesis. It has generally been assumed that the regulation of transcription underlies L-LTM and LTM. Chapter 2 of this thesis demonstrates that transgenic mice with inhibited ERK MAP Kinase pathway activity in the cortex and CA1 region of the hippocampus show inhibited LTM and L-LTP. Moreover, the L-LTP phenotype resembles a deficit in translation and not transcription. Experiments using hippocampal cultured cells demonstrate that neuronal activity induces translation of a large number of mRNAs in an ERK MAP Kinase pathway-dependent manner via phosphorylation of the translation factors S6, elF4E and 4E-BP1. Increased phosphorylation of translation factors was observed along with increased translation after the induction of L-LTP; lastly, LTM formation occurred concomitantly with ERK MAP Kinase pathway-dependent phosphorylation of S6 and elF4E. Chapter 3 extends these findings to demonstrate that other stimuli that cause protein synthesis-dependent forms of plasticity also upregulate protein synthesis via the same mechanisms.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2005

Author dc:creator

• Govindarajan, Arvind

Advisor dc:contributor.advisor

• Susumu Tonegawa.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/34573

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/34573