Down-regulation of protocadherin-α A isoforms in mice changes contextual fear conditioning and spatial working memory
Abstract
Diverse protocadherins (Pcdhs), which are encoded as a large cluster (composed of alpha, beta and gamma 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-alpha proteins and examined their behavioral abnormalities. There are two alternative splicing variants of the Pcdh-alpha constant region, Pcdh-alpha A and B isoforms, with different cytoplasmic tails. Pcdh-alpha(DeltaBneo/DeltaBneo) mice, in which the Pcdh-alpha B splicing variant was absent and the Pcdh-alpha 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-alpha(DeltaAneo/DeltaAneo) mice, which lacked 57 amino acids of the Pcdh-alpha A cytoplasmic tail. These learning abnormalities were, however, not seen in Pcdh-alpha(DeltaB/DeltaB) mice [in which the neomycin-resistance (neo) gene cassette was removed from the Pcdh-alpha(DeltaBneo/DeltaBneo) alleles], in which the expression level of the Pcdh-alpha A isoforms was recovered, although the Pcdh-alpha B isoforms were still completely missing in the brain. In addition, the amount of 5-hydroxytryptamine increased in the hippocampus of the hypomorphic Pcdh-alpha A mutant mice but not in recovery Pcdh-alpha(DeltaB/DeltaB). These results suggested that the level of Pcdh-alpha 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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One putative region of selection along chromosome A1 is denoted by a pair of protocadherin genes (PCDHA1 and PCDHB4).
“One putative region of selection along chromosome A1 (chrA1) (Fig. 3) is denoted by a pair of protocadherin genes (PCDHA1 and PCDHB4), which establish and maintain specific neuronal connections and have implications for synaptic specificity, serotonergic innervation of the brain, and fear conditioning (43).”
From Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication (2014) · cites this paper as [43]
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- Authors
- Fukuda, E., Hamada, S., Hasegawa, S., Katori, S., Sanbo, M., Miyakawa, T., Yamamoto, T., Yamamoto, H., Hirabayashi, T., & Yagi, T.
- Affiliations
- The University of Osaka (JP)
- Fukuoka Women's University (JP)
- National Institute for Physiological Sciences (JP)
- Fujita Health University (JP)
- Yokohama City University (JP)
- Tokyo Institute of Psychiatry (JP)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2008-10
- Volume
- 28
- Issue
- 7
- Pages
- 1362-1376
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W2157583031
- Cited by
- 64
- References
- 39
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 11 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 5
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- alternative splicing, contextual fear conditioning, spatial working memory, hippocampus, serotonin, learning and memory, cytoplasmic tail
- MeSH terms
- Animals, Brain, Cell Line, Conditioning, Psychological, Fear, Humans, Male, Memory Disorders, Memory, Short-Term, Nerve Tissue Proteins, Receptors, Cell Surface, Space Perception, Down-Regulation, Cadherins, Alternative Splicing, Maze Learning, Protein Isoforms, Mice, Gene Knockdown Techniques
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