Neuronal nicotinic receptors: insights gained from gene knockout an knocking mutant mice

Drago, John; McColl, Craig D.; Horne, Malcolm; Finkelstein, David I.; Ross, Shelley

doi:10.1007/s00018-003-2259-9

Cited by 64 publications

(40 citation statements)

References 100 publications

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“…The vertebrate nicotinic AChRs (nAChRs) containing the ␣7 subunit are localized in several brain areas that are involved in cognitive function (Dominguez del Toro et al, 1994;Drago et al, 2003), and their abnormal functionality has been related to several neuropathologies, including AD (Quirion et al, 1986;Perry et al, 1987Perry et al, , 1995. For instance, ␣7nAChRs colocalize with AD plaques (Wang et al, 2000a) and correlate with neurons that accumulate A␤ (Wevers et al, 1999) and with neurons most vulnerable to A␤ toxicity (D'Andrea and Nagele, 2006).…”

Section: Discussionmentioning

confidence: 99%

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Rebolledo¹,

Aldunate²,

Kohn³

et al. 2011

Journal of Neuroscience

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Alzheimer's disease and inclusion body myositis (IBM) are disorders frequently found in the elderly and characterized by the presence of amyloid-␤ peptide (A␤) aggregates. We used Caenorhabditis elegans that express A␤ in muscle cells as a model of IBM, with the aim of analyzing A␤-induced muscle pathology and evaluating the consequences of modulating A␤ aggregation.First, we tested whether the altered motility we observed in the A␤ transgenic strain could be the result of a compromised neuromuscular synapse. Our pharmacological analyses show that synaptic transmission is defective in our model and suggest a specific defect on nicotine-sensitive acetylcholine receptors (AChRs). Through GFP-coupled protein visualization, we found that synaptic dysfunction correlates with mislocalization of ACR-16, the AChR subunit essential for nicotine-triggered currents.Histological and biochemical analysis allowed us to determine that copper treatment increases the amyloid deposits and decreases A␤ oligomers in this model. Furthermore, copper treatment improves motility, ACR-16 localization, and synaptic function and delays A␤-induced paralysis. Our results indicate that copper modulates A␤-induced pathology and suggest that A␤ oligomers are triggering neuromuscular dysfunction. Our findings emphasize the importance of neuromuscular synaptic dysfunction and the relevance of modulating the amyloidogenic component as an alternative therapeutic approach for this debilitating disease.

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Section: Discussionmentioning

confidence: 99%

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Rebolledo¹,

Aldunate²,

Kohn³

et al. 2011

Journal of Neuroscience

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“…Compensatory changes in other cholinergic system components have not been reported in mice with null mutations of nicotinic receptor subtypes. On the other hand, a gain of function mutation of the α7 subunit may have led to compensatory changes in developmental factors while deletion of the α4 subunit resulted in an apparent compensatory down regulation of glutamatergic neurotransmission (Drago et al, 2003).…”

Section: Compensatory Changesmentioning

confidence: 99%

Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

et al. 2008

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The α7 subtype of nicotinic receptor is highly expressed in the hippocampus where it is purported to modulate release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The α7 receptormediated release of GABA is thought to contribute to hippocampal inhibition (gating) of response to repetitive auditory stimulation. This hypothesis is supported by observations of hippocampal auditory gating deficits in mouse strains with low levels of hippocampal α7 receptors compared to strains with high levels of hippocampal α7 receptors. The difficulty with comparisons between mouse strains, however, is that different strains have different genetic backgrounds. Thus, the observed interstrain differences in hippocampal auditory gating might result from factors other than interstrain variations in the density of hippocampal α7 receptors. To address this issue, hippocampal binding of the α7 receptor-selective antagonist α-bungarotoxin as well as hippocampal auditory gating characteristics were compared in C3H wild type and C3H α7 receptor null mutant heterozygous mice. The C3H α7 heterozygous mice exhibited significant reductions in hippocampal α7 receptors levels and abnormal hippocampal auditory gating compared to the C3H wild type mice. In addition, a general increase in CA3 pyramidal neuron responsivity was observed in the heterozygous mice compared to the wild type mice. These data suggest that decreasing hippocampal α7 receptor density results in a profound alteration in hippocampal circuit function.

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“…The recent development of genetically engineered mice with the targeted deletion of specific subunits (knockout mice, Ko) or mutations in critical receptor domains (knockin mice, Kin), as well as Ko mice made to re-express nAChR subunits in selected brain regions by means of lentiviral vectors, has led to the in vivo identification of complex subtypes and allowed the study of individual subtypes in specific cells and complex neurobiological systems (reviewed in [1,[9][10][11][12]). …”

Section: Introductionmentioning

confidence: 99%

Structural and functional diversity of native brain neuronal nicotinic receptors

Gotti

Clementi

Fornari

et al. 2009

Biochemical Pharmacology

421

430

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Although some of the neural circuits involved in the acute and chronic effects of nicotine have been identified, much less is known about which native nAChR subtypes are involved in specific physiological functions and pathophysiological conditions.We briefly review some recent findings concerning the structure and function of native nAChRs, focusing on the subtypes identified in the meso-striatal and habenulo-interpeduncular pathways, two systems involved in nicotine reinforcement and withdrawal. We also discuss recent findings concerning the effect of chronic nicotine on the expression of native subtypes.

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Neuronal nicotinic receptors: insights gained from gene knockout an knocking mutant mice

Cited by 64 publications

References 100 publications

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Copper Reduces A Oligomeric Species and Ameliorates Neuromuscular Synaptic Defects in a C. elegans Model of Inclusion Body Myositis

Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

Structural and functional diversity of native brain neuronal nicotinic receptors

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