Galantamine promotes adult hippocampal neurogenesis via M1 muscarinic and α7 nicotinic receptors in mice

Abstract

Galantamine, an inhibitor of acetylcholinesterase, promotes hippocampal neurogenesis, but the exact mechanism for this is not known. In the present study, we examined the mechanisms underlying the effects of acute galantamine on neurogenesis in the mouse hippocampus. Galantamine (3 mg/kg) increased the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the subgranular zone of the dentate gyrus. This effect was blocked by the muscarinic receptor antagonist scopolamine and the preferential M1 muscarinic receptor antagonist telenzepine, but not by the nicotinic receptor antagonists mecamylamine and methyllycaconitine. Galantamine did not alter the ratio of neuronal nuclei (NeuN)- or glial fibrillary acidic protein (GFAP)-positive cells to BrdU-labeled cells in the subgranular zone and granule cell layer. Galantamine (1, 3 mg/kg) promoted the survival of 2-wk-old newly divided cells in mice in the granule cell layer of the dentate gyrus, whereas it did not affect the survival of newly divided cells at 1 and 4 wk. Galantamine-induced increases in cell survival were blocked by the α7 nicotinic receptor antagonist methyllycaconitine, but not by scopolamine. Bilateral injection of recombinant IGF2 into the dentate gyrus of the hippocampus mimicked the effects of galantamine. The effects of galantamine were blocked by direct injection of the IGF1 receptor antagonist JB1. These findings suggest that galantamine promotes neurogenesis via activation of the M1 muscarinic and α7 nicotinic acetylcholine receptors. The present study also suggests that IGF2 is involved in the effects of galantamine on the survival of 2-wk-old immature cells in the granule cell layer.

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

“…Increased α7 nAChR activity should reduce proliferation, but that is contrary to the enhanced proliferation we observed in the MCAO group. One possible explanation may be that activated M1 AChR augments cell proliferation to neutralize the negative effect of α7 nAChR [57]. Therefore, the balance between M1 AChR and α7 AChR deserves more research.…”

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

“…The dentate gyrus receives input from the basal forebrain through GABAergic and cholinergic projection neurons (Bao et al 2017; Cooper-Kuhn et al 2004), and the infusion of fibroblasts releasing acetylcholine (ACh) into the hippocampus reverses cognitive decline (Dickinson-Anson et al 2003). Anti-cholinesterases, which inhibit the breakdown of acetylcholine, increase adult neurogenesis (Kotani et al 2006) and promote survival of immature neurons through the α7 subtype of nicotinic ACh receptors (nAChRs) (Kita et al 2014). By contrast, constitutive activation of the α7 nAChR results in increased apoptosis in the CNS of neonatal mice (Orr-Urtreger et al 2000).…”

Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition

“…Hippocampal overexpression of IGF2 ameliorated sucrose consumption and immobility time in the forced swim test displays of depression-like behaviors induced by chronic restraint stress in rats (Luo et al, 2015). Administration of IGF2 also increased neurogenesis in the hippocampus, a process that may contribute to the action of antidepressants (Bracko et al, 2012; Chen et al, 2007; Ferrón et al, 2015; Kita et al, 2014). In vivo administration of IGF2 in the hippocampus increased the expression of several neurotrophins and growth factors, such as brain-derived neurotrophic factor (BDNF) (Mellott et al, 2014).…”