Growth hormone signaling and hippocampal neurogenesis: Insights from genetic models

Abstract

Adult hippocampal neurogenesis (AHN) is modulated by a variety of factors through effects on the proliferation-differentiation-survival regulatory axis. We have employed growth hormone receptor knockout (GH-R-/-) and suppressor of cytokine signaling-2 transgenic (SOCS-2 Tg) mice as models of altered GH-signaling to assess their affects on basal and exercised-induced hippocampal neurogenesis. Assessment of proliferation 24-h after 7-days of bromodeoxyuridine (BrdU) labeling with or without voluntary running showed that the density of BrdU(+) cells in the subgranular zone remained unchanged between genotypes in control housing, while running induced significant increases in BrdU-labeled cells in WT, GH-R-/-, and SOCS-2 Tg mice. The proportion of BrdU/doublecortin and BrdU/S100beta cells did not vary between genotype or running conditions at this time-point. Assessment of cell survival 28-days after BrdU labeling showed that SOCS-2 Tg animals had significantly higher BrdU(+) cell densities in the granule cell layer compared to WT and GH-R-/- animals in control housing and after voluntary running. There were no differences in cell survival between WT and GH-R-/- mice with or without running. Mature phenotype analysis showed similar proportions of BrdU/NeuN and BrdU/S100beta in all groups. While SOCS-2 Tg mice had similar social interaction behaviors and sensorimotor gating, they appeared to be less anxious with heightened basal locomotor activity and showed enhanced performance in the Morris watermaze test. Overall, our data indicated that mice over-expressing SOCS-2 showed increased survival of neurons generated during AHN, which correlated with improved performance in a hippocampal-dependent cognitive task. Furthermore, voluntary running increased AHN in WT, SOCS-2 Tg, and serum-IGF-1-deficient GH-R-/- mice.

Is integration and survival of newborn neurons the bottleneck for effective neural repair by endogenous neural precursor cells?

“…In the adult its expression is primarily in the dentate gyrus and hippocampal CA3 region, suggesting it plays a role in adult neurogenesis. Overexpression of SOCS2 increased numbers of newborn adult hippocampal neurons without affecting their differentiation or proliferation of neural precursor cells (Ransome and Turnley, 2008). These results are in keeping with the idea that enhancing neurite outgrowth and complexity may enhance survival and integration of newborn neurons.…”

Control of Cell Survival in Adult Mammalian Neurogenesis

“…Storeoperated calcium channels (SOCS)-2 have been found to interact with the cytoplasmic domain of IGF-1 receptor and are thought to be involved in the regulation of IGF-1-receptor-mediated cell signaling. Transgenic mice overexpressing SOCS-2 show increased survival of adult-born hippocampal neurons, which correlates with improved performance in a hippocampal-dependent cognitive task (Ransome and Turnley 2008 Figure 2. A multitude of factors regulates adult neurogenesis by controlling proliferation, fate determination, and survival of cells.…”

Ghrelin Regulation in Epilepsy

“…It firstly promotes the release of glutamate; secondly, mitogen-activated protein kinase (MAPK) cascade and finally it increases the rate of proliferation of cell's progenitors (Aberg et al, 2000(Aberg et al, , 2003Choi et al, 2008;Kurihara et al, 2000). Probably the involvement of GH signalling not regards the GH-receptor (GHR); in fact, an increase of neuronal proliferation in the subgranular zone of the dentate gyrus has been shown in GHR knockout mice (Ransome & Turnley, 2008). The neuronal plasticity related to GH suggests the possibility of therapeutic interventions against neurodegenerative disorders in the older age; however, recent data also indicate that these newly generated neurons are integrated into epileptogenic networks in animal models (Siebzehnrubl & Blumcke, 2008), suggesting that neurogenesis contributes to promote susceptibility to seizures.…”