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.
Highlights
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family of growth factors that includes EGF, transforming growth factor (TGF)-a, amphiregulin, betacelulin, and neuregulin [1,2,3]
HB-EGF protein was undetectable beyond the background level in the cell layer of CA1, CA3, and dentate gyrus (DG) of KO mice hippocampus (Fig. 1g)
These results corresponded with a previous report which detected the Six3 expression in the ventral forebrain and basal ganglion [24]
Summary
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family of growth factors that includes EGF, transforming growth factor (TGF)-a, amphiregulin, betacelulin, and neuregulin [1,2,3]. EGF family members act as neurotrophic molecules, serving to enhance stem cell proliferation and neural differentiation, and they influence synaptic plasticity [7,8,9]. HB-EGF promotes the survival of dopaminergic neurons, an action mediated by mitogen-activated protein kinase (MAPK) as well as by the Akt signaling pathway [14]. For these reasons, HB-EGF may be an important contributor to neural development
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