Cholinergic receptors: Functional role of nicotinic ACh receptors in brain circuits and disease

Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop F2-08, Research Triangle Park, NC, 27709, USA, .
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 01/2013; 465(4). DOI: 10.1007/s00424-012-1200-1
Source: PubMed


The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection.

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    • ") ; ( ii ) the cholinergic deficit is closely related to the pathogenesis of AD ( Levey , 1996 ; Clader and Wang , 2005 ; Oddo and LaFerla , 2006 ; Yakel , 2013 ) ; ( iii ) Ab has a picomolar affinity for a7 - nAChRs ( Wang et al . , 2000 ) ; ( iv ) Ab modulates a7 - nAChR function ( Dougherty et al . "
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    ABSTRACT: For several years Amyloid-beta peptide (Aβ) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aβ levels have been unsuccessful. Moreover, Aβ is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aβ and its physiological receptors, focusing on α7-nAchRs. According to this vision, when Aβ cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aβ removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aβ in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; 307. DOI:10.1016/j.neuroscience.2015.08.039 · 3.36 Impact Factor
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    • "Several nicotinic acetylcholine receptor (nAChR) subtypes are expressed widely along the entire neuraxis and are involved in many of the physiologic functions of the central and peripheral nervous systems (Albuquerque et al., 2009; Hurst et al., 2013). nAChR activity controls important aspects of synaptic function and brain development, including the proliferation and differentiation of neural progenitors, neural migration, and neuronal maturation (Griguoli and Cherubini, 2012; Picciotto et al., 2012; Yakel, 2013). Furthermore, nAChR dysfunction may play an important role in a variety of neurologic diseases, including neurodegenerative and psychiatric diseases (Gotti and Clementi, 2004; Lewis and Picciotto, 2013). "
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    ABSTRACT: We examined α7β2-nicotinic acetylcholine receptor (α7β2-nAChR) expression in mammalian brain and compared pharmacological profiles of homomeric α7-nAChR and of α7β2-nAChR. α-Bugarotoxin affinity purification or immunoprecipitation with anti-α7 subunit antibodies (Abs) were used to isolate nAChR containing α7 subunits from rat or human brain samples. α7β2-nAChR were detected in forebrain, but not other tested regions, from both species, based on western blot analysis of isolates using β2 subunit-specific Abs. Abs specificity was confirmed in control studies using subunit-null mutant mice or cell lines heterologously expressing specific, human nAChR subtypes and subunits. Functional expression in Xenopus oocytes of concatenated pentameric (α7)5-, (α7)4(β2)1-, and (α7)3(β2)2-nAChR was confirmed using two-electrode voltage-clamp recording of responses to nicotinic ligands. Importantly pharmacological profiles were indistinguishable for concatenated (α7)5-nAChR or for homomeric α7-nAChR constituted from unlinked α7 subunits. Pharmacological profiles were similar for (α7)5-, (α7)4(β2)1-, and (α7)3(β2)2-nAChR except for diminished efficacy of nicotine (normalized to acetylcholine efficacy) at α7β2- vs. α7-nAChR. This study represents the first direct confirmation of α7β2-nAChR expression in human and mouse forebrain, supporting previous mouse studies that suggested relevance of α7β2-nAChR in Alzheimer's disease etiopathogenesis. These data also indicate that α7β2-nAChR subunit isoforms with different α7:β2 subunit ratios have similar pharmacological profiles to each other, and to α7 homopentameric nAChR. This supports the hypothesis that α7β2-nAChR agonist activation predominantly or entirely reflects binding to α7/α7 subunit interface sites.
    Molecular pharmacology 07/2014; 86(3). DOI:10.1124/mol.114.093377 · 4.13 Impact Factor
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    • "There are two types of AChRs: the nAChR and mAChR. Both receptors allow ACh to change the electrical activity of the target cells and to affect other processes through intracellular signaling cascades (Dajas-Bailador and Wonnacott, 2004; Gulledge and Stuart, 2005; Intskirveli and Metherate, 2012; Thiele, 2013; Yakel, 2013). However, these receptors function in fundamentally different ways. "
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    ABSTRACT: Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.
    Frontiers in Neural Circuits 03/2014; 8:17. DOI:10.3389/fncir.2014.00017 · 3.60 Impact Factor
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