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

Inoue N, Nakao H, Migishima R, Hino T, Matsui M, Hayashi F, Nakao K, Manabe T, Aiba A, Inokuchi K - Mol Brain (2009)

Bottom Line: 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.These 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Mitsubishi Kagaku Institute of Life Sciences, MITILS, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. inouenok@yahoo.co.jp

ABSTRACT

Background: 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, 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 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.

Results: In 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.

Conclusion: These 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.

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KO mice show faster within-session freezing decrement. a, Mice were conditioned by administration of 5 footshocks and the freezing response was measured after 24 h without footshock for 15 min. *, P < 0.05, t test. b, KO mice showed normal freezing decrement in the consolidation of extinction. Mice were conditioned by 5 footshocks. Mice were exposed to the conditioning chamber without footshock every day to assess freezing response. The mean percentage of time spent in freezing during the 6 min test is plotted. The number of mice used for each experiment is indicated in parentheses.
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Figure 7: KO mice show faster within-session freezing decrement. a, Mice were conditioned by administration of 5 footshocks and the freezing response was measured after 24 h without footshock for 15 min. *, P < 0.05, t test. b, KO mice showed normal freezing decrement in the consolidation of extinction. Mice were conditioned by 5 footshocks. Mice were exposed to the conditioning chamber without footshock every day to assess freezing response. The mean percentage of time spent in freezing during the 6 min test is plotted. The number of mice used for each experiment is indicated in parentheses.

Mentions: Fear memory retrieval without unconditioned stimulus initiates two opposite processes: reconsolidation and extinction [31,32,36]. Reconsolidation acts to stabilize memory, while extinction tends to weaken the expression of original memory. We next determined whether deletion of the short form of Vesl-1 affected the extinction of fear-conditioned memory. Mice received five footshocks during training day and freezing behavior was assessed 24 h later via 15-min exposure to the context (Figure 7a). KO mice showed faster within-session freezing decrement.


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

Inoue N, Nakao H, Migishima R, Hino T, Matsui M, Hayashi F, Nakao K, Manabe T, Aiba A, Inokuchi K - Mol Brain (2009)

KO mice show faster within-session freezing decrement. a, Mice were conditioned by administration of 5 footshocks and the freezing response was measured after 24 h without footshock for 15 min. *, P < 0.05, t test. b, KO mice showed normal freezing decrement in the consolidation of extinction. Mice were conditioned by 5 footshocks. Mice were exposed to the conditioning chamber without footshock every day to assess freezing response. The mean percentage of time spent in freezing during the 6 min test is plotted. The number of mice used for each experiment is indicated in parentheses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2663561&req=5

Figure 7: KO mice show faster within-session freezing decrement. a, Mice were conditioned by administration of 5 footshocks and the freezing response was measured after 24 h without footshock for 15 min. *, P < 0.05, t test. b, KO mice showed normal freezing decrement in the consolidation of extinction. Mice were conditioned by 5 footshocks. Mice were exposed to the conditioning chamber without footshock every day to assess freezing response. The mean percentage of time spent in freezing during the 6 min test is plotted. The number of mice used for each experiment is indicated in parentheses.
Mentions: Fear memory retrieval without unconditioned stimulus initiates two opposite processes: reconsolidation and extinction [31,32,36]. Reconsolidation acts to stabilize memory, while extinction tends to weaken the expression of original memory. We next determined whether deletion of the short form of Vesl-1 affected the extinction of fear-conditioned memory. Mice received five footshocks during training day and freezing behavior was assessed 24 h later via 15-min exposure to the context (Figure 7a). KO mice showed faster within-session freezing decrement.

Bottom Line: 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.These 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Mitsubishi Kagaku Institute of Life Sciences, MITILS, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. inouenok@yahoo.co.jp

ABSTRACT

Background: 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, 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 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.

Results: In 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.

Conclusion: These 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.

Show MeSH
Related in: MedlinePlus