Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus

Abstract

GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2 0 -deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increased Igf1 and Gfap mRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a (Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2 (Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs (Glul )). However, IGF1R was correlated with the expression of Dor, Nr2a, Sapap2, Gs and Gfap. In summary, although local bGH expression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose-response curve and cell-specific expression of bGH.

Different modes of GH administration influence gene expression in the male rat brain

“…In our previous studies, we have shown that Hbb is robustly regulated by GH in female rats (Walser et al 2012). Although endogenous neuronal (non-erythrocyte) hemoglobin has been found in neurons of rodents and human brain, its function is still not fully clear (Richter et al 2009, He et al 2010.…”

Voluntary wheel running delays brain atrophy in aged mice

“…Exercise increases the uptake of IGF-1 [35] from the bloodstream into various brain regions. Although the detailed mechanisms of the reduced brain degeneration remain unclear, it may be related to the attenuation of aging-related neuronal death [36] and the jump-start of hippocampus neuron proliferation [37]. (2) It is worth mentioning that not all intensity-associated stress levels show the same effects on neuroplasticity.…”

The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor–Binding Proteins in the Nervous System

“…25 However overexpression of GH in mouse hippocampus is associated with only a modest change in local IGF-I expression. 26…”

“…25 However overexpression of GH in mouse hippocampus is associated with only a modest change in local IGF-I expression. 26 Insulin-like growth factor inhibits GH secretion through endocrine negative feedback, crossing the fenestrated sinusoid capillaries of the anterior pituitary, and inhibiting spontaneous and GHRH-stimulated GH release by somatotrophs. 16 It is also possible that there is negative feedback by IGF-I on GHRH in the hypothalamus.…”