Requirement of the immediate early gene vesl-1S/homer-1a for fear memory formation

Naoko Inoue,Fumihiko Hayashi,Atsu Aiba,Rika Migishima,Toshiya Manabe,Minoru Matsui,Kaoru Inokuchi,Kazuki Nakao,Toshiaki Hino,Harumi Nakao

doi:10.1186/1756-6606-2-7

Abstract

BackgroundThe formation of long-term memory (LTM) and the late phase of long-term potentiation (L-LTP) depend on macromolecule synthesis, translation, and transcription in neurons. vesl-1S (VASP/Ena-related gene upregulated during seizure and LTP, also known as homer-1a) is an LTP-induced immediate early gene. The short form of Vesl (Vesl-1S) is an alternatively spliced isoform of the vesl-1 gene, which also encodes the long form of the Vesl protein (Vesl-1L). Vesl-1L is a postsynaptic scaffolding protein that binds to and modulates the metabotropic glutamate receptor 1/5 (mGluR1/5), the IP3 receptor, and the ryanodine receptor. Vesl-1 null mutant mice show abnormal behavior, which includes anxiety- and depression-related behaviors, and an increase in cocaine-induced locomotion; however, the function of the short form of Vesl in behavior is poorly understood because of the lack of short-form-specific knockout mice.ResultsIn this study, we generated short-form-specific gene targeting (KO) mice by knocking in part of vesl-1L/homer-1c cDNA. Homozygous KO mice exhibited normal spine number and morphology. Using the contextual fear conditioning test, we demonstrated that memory acquisition and short-term memory were normal in homozygous KO mice. In contrast, these mice showed impairment in fear memory consolidation. Furthermore, the process from recent to remote memory was affected in homozygous KO mice. Interestingly, reactivation of previously consolidated fear memory attenuated the conditioning-induced freezing response in homozygous KO mice, which suggests that the short form plays a role in fear memory reconsolidation. General activity, emotional performance, and sensitivity to electrofootshock were normal in homozygous KO mice.ConclusionThese results indicate that the short form of the Vesl family of proteins plays a role in multiple steps of long-term, but not short-term, fear memory formation.

Highlights

The formation of long-term memory (LTM) and the late phase of long-term potentiation (L-LTP) depend on macromolecule synthesis, translation, and transcription in neurons. vesl-1S (VASP/Ena-related gene upregulated during seizure and LTP, known as homer-1a) is an LTP-induced immediate early gene
The short forms of the Vesl protein contain the EVH-1 domain, they lack the C-terminal coiled-coil domain; the inducible short form Vesl-1 proteins are believed to act as endogenous dominant-negative regulators, as they compete with the long form Vesl protein to bind to receptors and channels
Short form Vesl is unique among the Vesl family proteins in that its expression is upregulated by various neural activities

Summary

Introduction

The formation of long-term memory (LTM) and the late phase of long-term potentiation (L-LTP) depend on macromolecule synthesis, translation, and transcription in neurons. vesl-1S (VASP/Ena-related gene upregulated during seizure and LTP, known as homer-1a) is an LTP-induced immediate early gene. Formation of long-term memory (LTM), but not short-term memory (STM), requires the synthesis of new RNA and protein [1]. The vesl-1L mRNA (long form) is constitutively expressed These proteins bind via their common N-terminal EVH-1 domain to group 1 metabotropic glutamate receptors (mGluRs), inositol tri-phosphate receptors (IP3Rs), ryanodine receptors (RyRs), the Shank family of postsynaptic scaffold proteins, and the C-type transient receptor potential channel (TRPC) [11,12,13,14,15,16,17]. Vesl-1L/ Homer1c contains additional C-terminal sequences, which include a coiled-coil domain and a leucine zipper, via which they associate to form homo- and heteromultimers to function as a scaffold protein and interact with receptors [11,12,14]. The short forms of the Vesl protein contain the EVH-1 domain, they lack the C-terminal coiled-coil domain; the inducible short form Vesl-1 proteins are believed to act as endogenous dominant-negative regulators, as they compete with the long form Vesl protein to bind to receptors and channels

Results

Discussion

Conclusion