Understanding mechanisms by which synapses are modified for long-term memory storage is crucial for explaining normal brain function as well as diseases and disorders of the brain. Many studies have established that new gene expression and new protein synthesis are critical for synaptic changes that underlie long-term memory. Recent studies indicate that proteolysis by the ubiquitin-proteasome pathway plays a critical role in long-term synaptic plasticity. The goal of this proposal is to elucidate the spatial and temporal roles of the proteasome and the interplay between protein synthesis and degradation in long-term synaptic plasticity We will use a highly suitable model system of mammalian long-term synaptic plasticity, late phase long-term potentiation (L-LTP) in the hippocampus. Our results show that inhibition of the proteasome enhances the early, translation-dependent induction part of L-LTP but inhibits the transcription-dependent maintenance phase of L-LTP. Proteasome-mediated enhancement of early part of L-LTP depends on NMDA receptor and cAMP-dependent protein kinase. Our data indicate that proteasome inhibition increases induction of L-LTP by stabilizing the locally synthesized proteins in the dendrites but interferes with local translation at later stages. Our results also show that inhibition of proteasome blocks transcription of brain-derived neurotrophic factor (BDNF), which is a cAMP-responsive element binding protein (CREB)-inducible gene. Furthermore, our results show that proteasome inhibitors block degradation of ATF4, a CREB repressor that is known to suppress L-LTP and memory. Thus, proteasome inhibition appears to block maintenance of L-LTP by hindering CREB-mediated transcription.
Our first aim i s to investigate the mechanism by which L-LTP induction is enhanced by proteasome inhibition and to identify the newly synthesized proteins stabilized by the proteasome. Under our second aim, we will test the idea that blockade of the proteasome impairs the maintenance of L-LTP by causing a buildup of negative regulators of plasticity such as translation repressors and by hindering transcription in the nucleus. Using a powerful combination of proteomic, molecular biological and electrophysiological studies the proposed experiments will address important, unanswered questions pertaining to the relationship between proteolysis and protein synthesis in long-term synaptic plasticity.

Public Health Relevance

Memories form when connections between nerve cells called synapses change. Recent discoveries show that regulation of proteins in the nerve cells by degradation plays a role in memory. Proteins are degraded by a part of the cell named proteasome when they are tagged by a little molecule called ubiquitin. Protein degradation is abnormal in many diseases and disorders of the brain. This research could help explain the memory loss that occurs in brain diseases and memory loss that happens in old age.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066583-03
Application #
8063177
Study Section
Special Emphasis Panel (ZRG1-IFCN-F (02))
Program Officer
Mamounas, Laura
Project Start
2009-05-15
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$317,275
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Vashisht, Anirudh; Bach, Svitlana V; Fetterhoff, Dustin et al. (2018) Proteasome limits plasticity-related signaling to the nucleus in the hippocampus. Neurosci Lett 687:31-36
Hegde, Ashok N (2017) Proteolysis, synaptic plasticity and memory. Neurobiol Learn Mem 138:98-110
Bach, Svitlana V; Tacon, P Ryan; Morgan, James W et al. (2015) Proteasome regulates transcription-favoring histone methylation, acetylation and ubiquitination in long-term synaptic plasticity. Neurosci Lett 591:59-64
Dong, Chenghai; Vashisht, Anirudh; Hegde, Ashok N (2014) Proteasome regulates the mediators of cytoplasmic polyadenylation signaling during late-phase long-term potentiation. Neurosci Lett 583:199-204
Hegde, Ashok N; Upadhya, Sudarshan C (2011) Role of ubiquitin-proteasome-mediated proteolysis in nervous system disease. Biochim Biophys Acta 1809:128-40
Hegde, Ashok N (2010) The ubiquitin-proteasome pathway and synaptic plasticity. Learn Mem 17:314-27