Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory

Emi Fukuda, Shun Hamada, Sonoko Hasegawa, Shota Katori, Makoto Sanbo, Tsuyoshi Miyakawa, Toshifumi Yamamoto, Hideko Yamamoto, Takahiro Hirabayashi, Takeshi Yagi

Research output: Contribution to journalArticle

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Abstract

Diverse protocadherins (Pcdhs), which are encoded as a large cluster (composed of α, β and γ clusters) in the genome, are localized to axons and synapses. The Pcdhs have been proposed to contribute to the generation of sophisticated neural networks and to regulate brain function. To address the molecular roles of Pcdhs in regulating individual behavior, here we generated knockdown mice of Pcdh-α proteins and examined their behavioral abnormalities. There are two alternative splicing variants of the Pcdh-α constant region, Pcdh-α A and B isoforms, with different cytoplasmic tails. Pcdh-αΔBneo/ΔBneo mice, in which the Pcdh-α B splicing variant was absent and the Pcdh-α A isoforms were down-regulated to approximately 20% of the wild-type level, exhibited enhanced contextual fear conditioning and disparities in an eight-arm radial maze. Similar abnormalities were found in Pcdh- αΔAneo/ΔAneo mice, which lacked 57 amino acids of the Pcdh-α A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-αΔB/ΔB mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-αΔBneo/ΔBneo alleles], in which the expression level of the Pcdh-α A isoforms was recovered, although the Pcdh-α B isoforms were still completely missing in the brain. In addition, the amount of 5-hydroxytryptamine increased in the hippocampus of the hypomorphic Pcdh-α A mutant mice but not in recovery Pcdh-α ΔB/ΔB. These results suggested that the level of Pcdh-α A isoforms in the brain has an important role in regulating learning and memory functions and the amount of 5-hydroxytryptamine in the hippocampus.

Original languageEnglish
Pages (from-to)1362-1376
Number of pages15
JournalEuropean Journal of Neuroscience
Volume28
Issue number7
DOIs
Publication statusPublished - 01-10-2008

Fingerprint

Short-Term Memory
Fear
Protein Isoforms
Down-Regulation
Tail
Hippocampus
Serotonin
Brain
Learning
Neomycin
Alternative Splicing
Synapses
Axons
Alleles
Spatial Memory
Conditioning (Psychology)
Genome
Amino Acids
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Fukuda, Emi ; Hamada, Shun ; Hasegawa, Sonoko ; Katori, Shota ; Sanbo, Makoto ; Miyakawa, Tsuyoshi ; Yamamoto, Toshifumi ; Yamamoto, Hideko ; Hirabayashi, Takahiro ; Yagi, Takeshi. / Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory. In: European Journal of Neuroscience. 2008 ; Vol. 28, No. 7. pp. 1362-1376.
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abstract = "Diverse protocadherins (Pcdhs), which are encoded as a large cluster (composed of α, β and γ clusters) in the genome, are localized to axons and synapses. The Pcdhs have been proposed to contribute to the generation of sophisticated neural networks and to regulate brain function. To address the molecular roles of Pcdhs in regulating individual behavior, here we generated knockdown mice of Pcdh-α proteins and examined their behavioral abnormalities. There are two alternative splicing variants of the Pcdh-α constant region, Pcdh-α A and B isoforms, with different cytoplasmic tails. Pcdh-αΔBneo/ΔBneo mice, in which the Pcdh-α B splicing variant was absent and the Pcdh-α A isoforms were down-regulated to approximately 20{\%} of the wild-type level, exhibited enhanced contextual fear conditioning and disparities in an eight-arm radial maze. Similar abnormalities were found in Pcdh- αΔAneo/ΔAneo mice, which lacked 57 amino acids of the Pcdh-α A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-αΔB/ΔB mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-αΔBneo/ΔBneo alleles], in which the expression level of the Pcdh-α A isoforms was recovered, although the Pcdh-α B isoforms were still completely missing in the brain. In addition, the amount of 5-hydroxytryptamine increased in the hippocampus of the hypomorphic Pcdh-α A mutant mice but not in recovery Pcdh-α ΔB/ΔB. These results suggested that the level of Pcdh-α A isoforms in the brain has an important role in regulating learning and memory functions and the amount of 5-hydroxytryptamine in the hippocampus.",
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Fukuda, E, Hamada, S, Hasegawa, S, Katori, S, Sanbo, M, Miyakawa, T, Yamamoto, T, Yamamoto, H, Hirabayashi, T & Yagi, T 2008, 'Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory', European Journal of Neuroscience, vol. 28, no. 7, pp. 1362-1376. https://doi.org/10.1111/j.1460-9568.2008.06428.x

Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory. / Fukuda, Emi; Hamada, Shun; Hasegawa, Sonoko; Katori, Shota; Sanbo, Makoto; Miyakawa, Tsuyoshi; Yamamoto, Toshifumi; Yamamoto, Hideko; Hirabayashi, Takahiro; Yagi, Takeshi.

In: European Journal of Neuroscience, Vol. 28, No. 7, 01.10.2008, p. 1362-1376.

Research output: Contribution to journalArticle

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T1 - Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory

AU - Fukuda, Emi

AU - Hamada, Shun

AU - Hasegawa, Sonoko

AU - Katori, Shota

AU - Sanbo, Makoto

AU - Miyakawa, Tsuyoshi

AU - Yamamoto, Toshifumi

AU - Yamamoto, Hideko

AU - Hirabayashi, Takahiro

AU - Yagi, Takeshi

PY - 2008/10/1

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