Alteration of hippocampal cell proliferation in mice lacking the β2 subunit of the neuronal nicotinic acetylcholine receptor

Abstract

Adult hippocampal neurogenesis declines with age in parallel with decreased performance on a variety of hippocampal-dependent tasks. We measured the rate of cellular proliferation in the hippocampus of mice lacking the beta 2-subunit of the nicotinic acetylcholine receptor (beta 2-/- mice) at three ages: young adult (3 months old), fully adult (7-10 months old), and aged (22-24 months old). Consistent with previous studies, we observed an age-related decline in hippocampal proliferation in both groups. However, in fully adult beta 2-/- mice a 43% reduction of granule cell proliferation was detected compared to age-matched controls. This was accompanied by a significant decrease in dentate gyrus area/section and the length of the granule cell layer in beta 2-/- mice. These alterations were not the result of a change in plasma corticosterone levels or expression of the neurotrophic factor BDNF in the dentate gyrus, two known regulators of hippocampal cell proliferation. Similarly, there was no increase in gliosis, abnormal myelination, or apoptotic cell death in the beta 2-/- animals, although there was a significant shift in the location of apoptotic cells in the dentate gyrus indicative of a change in neuronal survival. These results suggest that the beta 2-subunit containing nicotinic acetylcholine receptors play an important role in regulating cell proliferation in the hippocampus and that endogenous acetylcholine may act to oppose the negative effects of normal aging and stress on cellular proliferation.

Sex steroids and the dentate gyrus

“…Conversely, systemic administration of the cholinergic agonist physostigmine increased dentate neurogenesis. The neurogenic effect of acetylcholine appears to involve nicotinic receptors containing the β2 subunit (Harrist et al, 2004), as well as m2, m3 and m4 muscarinic receptors (Ma et al, 2000;Mohapel et al, 2005). Consistent with these findings, ovariectomy upregulated m4 receptors in the dentate gyrus, whereas estrogen treatment restored m4 binding to the level of the sham group (El-Bakri et al, 2002).…”

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress

“…A combination of pharmacological and molecular genetic experiments has suggested that β2* nAChRs contribute to stress-induced behaviors and may contribute to the effects of antidepressant medications effective in human patients Harrist et al, 2004). The effect of α7 nAChRs on behaviors related to depression is more complex, however.…”

A Novel Cognitive Enhancer, ZSET1446/ST101, Promotes Hippocampal Neurogenesis and Ameliorates Depressive Behavior in Olfactory Bulbectomized Mice

“…For example, injection into the lateral ventricle of IgG-saporin, which causes selective degeneration of cholinergic neurons, reduces DG neurogenesis with concurrent impairment of spatial memory in rodents (Cooper-Kuhn et al, 2004). The nAChRs also play a critical role to regulate neurogenesis based on a decline in hippocampal cell proliferation in mice lacking the nAChR ␤2 subunit (Harrist et al, 2004). In addition, restoration of neurogenesis in OBX was observed after chronic administration of citalopram, a serotonin-selective reuptake inhibitor (Jaako-Movits et al, 2006).…”