Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice.
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.
Oyagi
Atsushi
A
Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
Oida
Yasuhisa
Y
Kakefuda
Kenichi
K
Shimazawa
Masamitsu
M
Shioda
Norifumi
N
Moriguchi
Shigeki
S
Kitaichi
Kiyoyuki
K
Nanba
Daisuke
D
Yamaguchi
Kazumasa
K
Furuta
Yasuhide
Y
Fukunaga
Kohji
K
Higashiyama
Shigeki
S
Hara
Hideaki
H
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
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