Induction of Dendritic Spines by  2-Containing Nicotinic Receptors

Abstract

Glutamatergic synapses are located mostly on dendritic spines in the adult nervous system. The spines serve as postsynaptic compartments, containing components that mediate and control the synaptic signal. Early in development, when glutamatergic synapses are initially forming, waves of excitatory activity pass through many parts of the nervous system and are driven in part by a class of heteropentameric β2-containing nicotinic acetylcholine receptors (β2*-nAChRs). These β2*-nAChRs are widely distributed and, when activated, can depolarize the membrane and elevate intracellular calcium levels in neurons. We show here that β2*-nAChRs are essential for acquisition of normal numbers of dendritic spines during development. Mice constitutively lacking the β2-nAChR gene have fewer dendritic spines than do age-matched wild-type mice at all times examined. Activation of β2*-nAChRs by nicotine either in vivo or in organotypic slice culture quickly elevates the number of spines. RNA interference studies both in vivo and in organotypic culture demonstrate that the β2*-nAChRs act in a cell-autonomous manner to increase the number of spines. The increase depends on intracellular calcium and activation of calcium, camodulin-dependent protein kinase II. Absence of β2*-nAChRs in vivo causes a disproportionate number of glutamatergic synapses to be localized on dendritic shafts, rather than on spines as occurs in wild-type. This shift in synapse location is found both in the hippocampus and cortex, indicating the breadth of the effect. Because spine synapses differ from shaft synapses in their signaling capabilities, the shift observed is likely to have significant consequences for network function.

Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome

“…Also, ␣ 7 -and ␤ 2 -subunits are instrumental in synapse and spine formation (36,37). Because of this, we tested whether the glutamatergic input to the LC is altered in Mecp2 Ϫ/Y mice and whether the cholinergic modulation was dysfunctional as well.…”

Visual Circuit Development Requires Patterned Activity Mediated by Retinal Acetylcholine Receptors

“…This suggests that disrupted spatiotemporal patterns of waves and not a decrease in wave frequency are the likely cause of circuit refinement defects in β2 −/− mice (Godfrey et al, 2009; Stafford et al, 2009). Further complicating matters, experiments employing β2 −/− mice suffer from the caveats typical of whole-animal knockouts, since β2-nAChRs are normally expressed throughout the brain and body, and glutamatergic synapse development is disrupted in the CNS of β2 −/− mice (Shah and Crair, 2008; Lozada et al, 2012) completely apart from their likely retinal wave deficits. These and other experimental ambiguities cast some doubt on the existence, form, and necessity of retinal waves for visual circuit development (Chalupa, 2009; Feller, 2009).…”

Nicotine induces dendritic spine remodeling in cultured hippocampal neurons

“…Although the present study focused on the semi-acute effect of nicotine within 2 h, more dramatic alterations such as spine density (Engert and Bonhoeffer 1999;Nagerl et al 2004) might be correlated to a more persistent type of plasticity. The relationship between the activity of nAChR and spine density has been recently shown; a region specific decrease in spine density is observed in b2 subunit deleted mice (Ballesteros-Yanez et al 2010;Lozada et al 2012). Notably, Lozada and colleagues have reported an acute (1 h) change in spine density in young mouse (P7) but not in older mouse (P15).…”

“…In contrast, long-term depression is correlated with the shrinkage or pruning of spines (Nagerl et al 2004;Zhou et al 2004). Recently, a relationship between the activity of nAChRs and spine density has been reported (Ballesteros-Yanez et al 2010;Lozada et al 2012). However, more acute change in spine morphology has yet to be studied.…”