Induction of Dendritic Spines by 2-Containing Nicotinic Receptors

Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0357, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2012; 32(24):8391-400. DOI: 10.1523/JNEUROSCI.6247-11.2012
Source: PubMed


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, calmodulin-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.

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    • "Regardless of the specific effect(s), nAChRs could regulate GABAergic transmission in at least two ways (not mutually exclusive ). First, nAChRs are known to regulate the development of the excitatory/inhibitory balance by regulating the maturation of both GABAergic transmission (Liu et al., 2006a) and dendritic spines (Lozada et al., 2012), during brain development . Second, because ADNFLE-linked mutations often potentiate the nAChR function, they may cause direct nAChRdependent hyperexcitability of the mature neocortex. "
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    • "At the synaptic level, recent studies have identified nicotinic receptor-dependent alterations in development of glutamatergic synapses (Lozada et al., 2012a; Morley and Mervis, 2013). Activation of postsynaptic α 7 -nicotinic receptors in cultured neurons or slice preparations promotes glutamatergic synapse formation, whereas knockout of the α 7 subunit in mice decreases the number of dendritic spines (Lozada et al., 2012b) and glutamatergic synapses, suggesting that cholinergic signaling through this nicotinic receptor subtype is normally important in modulating the number of excitatory synapses. Inhibitory effects of CBs would be expected to affect formation of glutamatergic synaptic transmission and plasticity of neuronal networks. "
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    • "Establishing molecular function classifications with PAN- THER pathway analysis [29] reveals that the primary interactions of mature b2 * nAChRs occur with structural proteins that are part of, and regulate the growth and assembly of, the cytoskeleton. These data are consistent with studies showing that b2 * nAChRs are involved in production and maintenance of dendritic spines during development [37]. Of particular interest are the cytoskeletal proteins that appear to Figure 3 Frequency distribution of correlations for proteins associated with b2 subunit Frequency distribution of calculated correlations between relative abundances of putative interacting proteins and b2 nAChR log 2 MRIPA was shown. "
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