Effect of nicotine on cerebellar granule neuron development

Abstract

To assess the role of nicotinic cholinergic receptors (nAChR) on neuronal maturation, nAChR expression and the direct effects of nAChR activation were examined in cerebellar external granular layer (EGL) precursors isolated in vitro. Treatment of EGL neuroblasts with nicotine elicited a concentration-dependent increase in DNA content and synthesis, implying an increase in cell numbers. Pretreatment of cultures with the nAChR antagonist dihydro-β-erythroidine (DHBE) attenuated nicotine-induced changes in DNA abundance and synthesis. Furthermore, chronic nicotine treatment for 4-7 days promoted EGL cell survival. Epibatidine but not cytisine stimulated granule neuroblast DNA synthesis and survival. Survival effects mediated by nicotine and epibatidine were attenuated by pre-treating cultures with DHBE. Immunocytochemical analysis revealed that EGL neurons possessed α3, but not α4, nAChR immunoreactivity. Quantitative autoradiography was used to determine which nAChRs are present during the period of granule cell neurogenesis in vivo. On postnatal day 5, the EGL was intensely labeled by [ 3 H]-epibatidine but virtually devoid of [ 3 H]-A85380 binding suggesting that a high concentration of α3 nAChRs is present in granule neuroblasts. The pharmacology of [ 3 H]-epibatidine displacement from EGL neurons also suggested an interaction with the α3-nAChR subunits. Together these data provide novel evidence that the activation of nAChRs directly affect the development of primary cerebellar neuroblasts and further suggest that the effects are mediated through the α3-nAChR subtype.

Nicotinic Receptor Abnormalities in the Cerebellar Cortex of Sudden Unexplained Fetal and Infant Death Victims—Possible Correlation With Maternal Smoking

“…More specifically, experimental studies have demonstrated that the dynamic sequence of morphological steps that regularly occur during CC development, mainly consisting in a progressive thinning until the disappearance of the EGL due to cell death or cell migration in the IGL, coincide with the maturation of the cholinergic system (Clos et al., 1989; Court et al., 1995). The activation of the α7-nAChR subtype appears to be particularly involved in the maturation of the granule layers (Caruncho et al., 1997; Opanashuk et al., 2001; Prestori et al., 2013). …”

White matter development and tobacco smoking in young adults: A systematic review with recommendations for future research

“…In mice, nicotine exposure upregulates the expression of nerve growth factor (NGF) and mRNA levels of its receptor tyrosine receptor kinase A (trkA) (Garrido et al, 2003), indicating that nicotine may enhance neuronal development. Other preclinical work suggests that neuroblasts in the cerebellum treated with nicotine increase the precursor cell's DNA synthesis significantly compared to untreated controls (Opanashuk et al, 2001), further indicating an enhancing role for nicotine in neurogenesis and myelination. Given greater rapidity of white-matter development during adolescence versus adulthood (Giedd et al, 1999), such nicotine-induced cell proliferation may differentially influence white-matter tissue structure and function across the lifespan.…”

Cigarette smoking and white matter microstructure

“…A possible mechanism by which smoking could raise FA draws from the following observations: 1) white matter matures through late adolescence faster than in adulthood (Benes 1989; Bartzokis and Lu 2009;); 2) nicotine acting at nAChRs can promote glial activity or proliferation (Garrido et al 2003; Liu et al 2005; Opanashuk et al 2001); and 3) nAChRs exist in subcortical white matter (Ding et al 2004). Oligodendrocyte precursor cells but not the oligodendrocytes and astrocytes into which these precursors differentiate do express nAChRs (Rogers et al 2001; reviewed Bartzokis 2007).…”