Multiorgan Autonomic Dysfunction in Mice Lacking the β2 and the β4 Subunits of Neuronal Nicotinic Acetylcholine Receptors

Wang, Xu; Orr‐Urtreger, Avi; Nigro, F.; Gelber, Shari E.; Sutcliffe, Cara Ballard; Armstrong, Dawna; Patrick, James W.; Role, Lorna W.; Beaudet, Arthur L.; Biasi, Mariella De

doi:10.1523/jneurosci.19-21-09298.1999

Cited by 273 publications

(235 citation statements)

References 38 publications

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“…Inactivation by gene targeting of ␣3 triggered major autonomic defects, resulting in 50% of lethality at birth, the remaining animals dying during the first 3 months of life (Xu et al, 1999a). Yet, the inactivation of either ␤2 or ␤4 did not cause lethal autonomic problems (Xu et al, 1999b). On the opposite, the double mutants ␤2 Ϫ/Ϫ / ␤4 Ϫ/Ϫ displayed a phenotype comparable to the ␣3 Ϫ/Ϫ mice.…”

Section: Some Functional Equivalences Revealed By Ko Animalsmentioning

confidence: 93%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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Section: Some Functional Equivalences Revealed By Ko Animalsmentioning

confidence: 93%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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“…Wild-type mice were from the C57BL/6 strain. Ephrin-A2, -A3, -A5, and ␤2 mutations were genotyped as previously described (Frisén et al, 1998;Xu et al, 1999;Feldheim et al, 2000;Cutforth et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

Pfeiffenberger

Yamada²,

Feldheim³

2006

J. Neurosci.

147

185

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The development of topographic maps in the primary visual system is thought to rely on a combination of EphA/ephrin-A interactions and patterned neural activity. Here, we characterize the retinogeniculate and retinocollicular maps of mice mutant for ephrins-A2, -A3, and -A5 (the three ephrin-As expressed in the mouse visual system), mice mutant for the ␤2 subunit of the nicotinic acetylcholine receptor (that lack early patterned retinal activity), and mice mutant for both ephrin-As and ␤2. We also provide the first comprehensive anatomical description of the topographic connections between the retina and the dorsal lateral geniculate nucleus. We find that, although ephrin-A2/A3/A5 triple knock-out mice have severe mapping defects in both projections, they do not completely lack topography. Mice lacking ␤2-dependent retinal activity have nearly normal topography but fail to refine axonal arbors. Mice mutant for both ephrin-As and ␤2 have synergistic mapping defects that result in a near absence of map in the retinocollicular projection; however, the retinogeniculate projection is not as severely disrupted as the retinocollicular projection is in these mutants. These results show that ephrin-As and patterned retinal activity act together to establish topographic maps, and demonstrate that midbrain and forebrain connections have a differential requirement for ephrin-As and patterned retinal activity in topographic map development.

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“…In the laboratory of Dr. Beaudet, mutant mouse lines were created in 129/SvEv cells, and were backcrossed to C57BL/6 mice for more than 7 generations (see Orr-Urtreger et al, 1997 andXu et al, 1999 for a more detailed explanation). For pharmacological experiments, the subjects were male C57BL/6 mice (ages 8-12 weeks).…”

Section: Subjectsmentioning

confidence: 99%

β2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

Portugal

Kenney

Gould

2008

Neurobiology of Learning and Memory

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Acute nicotine enhances contextual fear conditioning, whereas withdrawal from chronic nicotine produces impairments. However, the nicotinic acetylcholine receptors (nAChR) that are involved in nicotine withdrawal deficits in contextual fear conditioning are unknown. The present study used genetic and pharmacological techniques to investigate the nAChR subtype(s) involved in the effects of nicotine withdrawal on contextual fear conditioning. β2 or α7 nAChR subunit knockout (KO) and corresponding wild-type (WT) mice were withdrawn from 12 days of chronic nicotine treatment (6.3 mg/kg/day), and trained with 2 conditioned stimulus (CS; 85 dB white noise) -unconditioned stimulus (US; 0.57mA footshock) pairings on day 13. On day 14, mice were tested for contextual and cued freezing. β2 KO mice did not show nicotine withdrawal-related deficits in contextual fear conditioning, in contrast to WT mice and α7 KO mice. A follow-up study investigated if nicotine withdrawal disrupts acquisition or recall of contextual fear conditioning. The high affinity nAChR antagonist dihydro-beta-erythroidine (DHβE; 3 mg/kg) was administered prior to training or testing to precipitate withdrawal in chronic nicotine-treated C57BL/6 mice. Deficits in contextual fear conditioning were observed in chronic nicotine-treated mice when DHβE was administered prior to training, but not when administered at testing. These results indicate that β2-containing nAChRs, such as the α4β2 receptor, mediate nicotine withdrawal deficits in contextual fear conditioning. In addition, nicotine withdrawal selectively affects acquisition but not recall or expression of the learned response.

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Multiorgan Autonomic Dysfunction in Mice Lacking the β2 and the β4 Subunits of Neuronal Nicotinic Acetylcholine Receptors

Cited by 273 publications

References 38 publications

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

β2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

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