Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity.

Spencer G Smith,Ashok N Hegde,Kathryn A Haynes

doi:10.3390/ijms21228543

Abstract

Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor activating transcription factor 4 (ATF4; also known as CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigate the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at serine-219 increases upon induction of cLTP and decreases about 30 min thereafter. Proteasome inhibitor β-lactone prevents the decrease in ATF4. We found that the phosphorylation of ATF4 is mediated by cAMP-dependent protein kinase. Our initial experiments towards the identification of the ligase that mediates ubiquitination of ATF4 revealed a possible role for β-transducin repeat containing protein (β-TrCP). Regulation of ATF4 degradation is likely to be a mechanism for determining the threshold for gene expression underlying maintenance of long-term synaptic plasticity and by extension, long-term memory.

Highlights

The ability of the nervous system to change the synaptic strength is called synaptic plasticity which allows it to store information for varying durations of time
We collected slices that were subjected to chemically induced long-term potentiation (cLTP)-inducing treatments and time-matched controls every 5 min during the first 30 min time period and carried out immunohistochemical experiments using an antibody raised against activating transcription factor 4 (ATF4) phosphorylated on Ser-219
We investigated the role of three kinases that are known to play a role in long-term synaptic plasticity: cAMP-dependent protein kinase (PKA) [17], cGMP-dependent protein kinase (PKG) [18], and extracellular signal-regulated kinase (ERK) [19]

Summary

Introduction

The ability of the nervous system to change the synaptic strength is called synaptic plasticity which allows it to store information for varying durations of time. Short-term synaptic plasticity, which underlies short-term memory, depends on the posttranslational modification of existing proteins in neurons [1]. Long-term synaptic plasticity, which forms the basis of long-term memory, relies upon the translation of pre-existing mRNAs at synaptic sites, such as dendrites, the transcription of new genes in the nucleus and the translation of newly transcribed mRNAs in the cytoplasm of neurons [2,3]. Several transcription factors play a role in the gene expression necessary for maintaining long-term synaptic plasticity [4], a transcription factor called cAMP-responsive element binding protein (CREB) has a key function in the hippocampus, a brain region critical for encoding new long-term memories [5,6]. CREB can induce the transcription of genes critical for long-term synaptic plasticity, only if the repression by ATF4 is relieved [8,9]

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Conclusion