title: Down-regulation of protocadherin-alpha 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.
authors.affiliation: KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Bioscience, Osaka University, 1-3 Yamadaoka, Suita 565-0871, Osaka, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Fukuda
authors.forename: Shun
authors.initials: S
authors.lastname: Hamada
authors.forename: Sonoko
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Shota
authors.initials: S
authors.lastname: Katori
authors.forename: Makoto
authors.initials: M
authors.lastname: Sanbo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hideko
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirabayashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yagi
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003213:Conditioning, Psychological / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005239:Fear / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D013028:Space Perception / Q000502:physiology*
chemical_list: D015820:Cadherins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface