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
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 . "
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.
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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). "
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.
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- "Moreover, it has been reported that when nicotinic receptors are present at the presynaptic level chronic exposure to nicotine increases the density of nicotinic receptors. Such increases in the number of nAChR demonstrate increased sensitization to nicotine and the nAChR also participate in the release of dopamine (DA) (Threlfell and Gragg, 2011; Yakel, 2013). "
ABSTRACT: Nicotine is an addictive substance of tobacco. It has been suggested that nicotine acts on glutamatergic (N-methyl-d-aspartate, NMDA) neurotransmission affecting dopamine release in the mesocorticolimbic system. This effect is reflected in neuroadaptative changes that can modulate neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) core (cNAcc) and shell (sNAcc) regions. We evaluated the effect of chronic administration of nicotine (4.23 mg/kg/day for 14 days) on NMDA activated currents in dissociated neurons from the PFC, and NAcc (from core and shell regions). We assessed nicotine blood levels by mass spectrophotometry and we confirmed that nicotine increases locomotor activity. An electrophysiological study showed an increase in NMDA currents in neurons from the PFC and core part of the NAcc in animals treated with nicotine compared to those of control rats. No change was observed in neurons from the shell part of the NAcc. The enhanced glutamatergic activity observed in the neurons of rats with chronic administration of nicotine may explain the increased locomotive activity also observed in such rats. To assess one of the possible causes of increased NMDA currents, we used magnesium, to block NMDA receptor that contains the NR2B subunit. If there is a change in percent block of NMDA currents, it means that there is a possible change in expression of NMDA receptor subunits. Our results showed that there is no difference in the blocking effect of magnesium on the NMDA currents. The magnesium lacks of effect after nicotinic treatment suggests that there is no change in expression of NR2B subunit of NMDA receptors, then, the effect of nicotine treatment on amplitude of NMDA currents may be due to an increase in the quantity of receptors or to a change in the unitary conductance, rather than a change in the expression of the subunits that constitute it. Synapse, 2014. © 2014 Wiley Periodicals, Inc.