title: Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.
abstract: Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. s-uchida@yamaguchi-u.ac.jp
authors.forename: Shusaku
authors.initials: S
authors.lastname: Uchida
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hara
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Otsuki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yamagata
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Hobara
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Higuchi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Shibata
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kida
authors.forename: Akira
authors.initials: A
authors.lastname: Nakai
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000503:physiopathology; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000076249:Heat Shock Transcription Factors; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; D014157:Transcription Factors; C103469:polysialyl neural cell adhesion molecule; C526452:ST8SiaII protein, mouse; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse