title: Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice.
abstract: Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Oyagi
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Oida
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kakefuda
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kitaichi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nanba
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004298:Dopamine / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D066246:ErbB Receptors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004298:Dopamine