title: Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development.
abstract: In the postnatal hippocampus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippocampal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2α-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippocampal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased cAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2α-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippocampus-associated cognitive impairment.
authors.affiliation: CNS, Astellas Research Institute of America LLC, Skokie, Illinois, USA.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Walton
authors.forename: Anoek
authors.initials: A
authors.lastname: de Koning
authors.forename: Xiuyuan
authors.initials: X
authors.lastname: Xie
authors.forename: Rick
authors.initials: R
authors.lastname: Shin
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyake
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.forename: Adam K
authors.initials: AK
authors.lastname: Gross
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kogan
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Heusner
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019886:Gastrin-Releasing Peptide
keywords: Alzheimer's disease; Bipolar disorder; Depression; Epilepsy; Gastrin-releasing peptide; Hippocampus; Neural stem cell; Neurogenesis; Schizophrenia