Article

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
ABSTRACT
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.

Full-text preview

Available from: link.springer.com
INVITED REVIEW
Cholinergic receptors: functional role of nicotinic ACh receptors
in brain circuits and disease
Jerrel L. Yakel
Received: 29 October 2012 /Revised: 3 December 2012 /Accepted: 3 December 2012 /Published online: 11 January 2013
#
Springer-Verlag Berlin Heidelberg (outside the USA) 2013
Abstract The neurotransmitter acetylcholine (ACh) can
regulate neuronal excitability throughout the nervous sys-
tem 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 pri-
mary cholinergic input to the hippocampus arises from the
medial septum and diagonal band of Broca, the acti vation of
which can activate both nAChRs and mAChRs in the hip-
pocampus and regulate synaptic communication and induce
oscillations that are thought to be imp ortant for cognitive
function. Dysfunction in the hippocampal cholinergic sys-
tem has been linked with cognitive deficits and a variety of
neurological disorders and diseases, including Alzheimers
disease and schizophrenia. My lab has focused on the role of
the nAChRs in regulating hippocampal function, from un-
derstanding the expression and fun ctional 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.
The hippocampus is critical for learning and memory [13,
14, 30, 63] and is an important site for co gnitive dysfunction
in a variety of neurodegenerative diseases including Alz-
heimers disease (AD) [62]. The hippocampal formation is
divided into four main subregions: the dentate gyrus, the
hippocampal proper (including CA1, CA2, and CA3
regions), the subicular complex, and the entorhinal cortex
(EC, including layers IVI). The main cholinergic input to
the hippocampus is from the medial septum and diagonal
band of Broca (MSDB) [40, 41], which innervates both
principal glut amatergic cells and inhibitory GABAergic
interneurons. In addition, the stimulation of the cholinergic
inputs to the hippocampus activates muscarinic acetylcho-
line receptors (mAChRs) on astrocytes in the CA1 stratum
oriens layer [3]. Besides the cholinergic input from the
MSDB, there is also a significant GABAergic input, and
the activation of the cholinergic and GABAergic inputs
from the MSDB is known to initiate and sustain network
oscillations (e.g., hippocampal theta rhythm) in vivo and in
vitro [5 , 19, 24, 41, 75, 76, 102]. Additionally, inputs to the
hippocampus from the EC are thought to regulate hippocampal
theta rhythm [5, 19].
Cholinergic receptors in the hippocampusfocus
on nicotinic acetylcholine receptor channels
The activation of acetylcholine (ACh) release will exert its
effect on a variety of different cys-loop ligand-gated nico-
tinic ACh receptor ch annels (nAChRs) an d G protein-
coupled mAChRs that are expressed on both neurons and
nonneuronal cells. The nAChRs are permeable to cations,
the activation of which depolarizes the cell and may induce
electrical firing. Some nAChRs are also permeable to calci-
um ions [21], and this increase in cytoplasmic calcium
levels can affect neurotransmitter release, signal transduc-
tion cascades, plasticity, cell survival, apoptosis, and gene
transcription [8, 23, 61
, 107, 108, 111].
J. L. Yakel (*)
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
e-mail: yakel@niehs.nih.gov
Pflugers Arch - Eur J Physiol (2013) 465:441450
DOI 10.1007/s00424-012-1200-1
Page 1
A variety of differ ent subtypes of G pr otein-c oupled
mAChRs have been shown to be expressed and regulate a
variety of ionic conductances (both depolarizing and hyper-
polarizing responses) and signal transduction cascad es in
hippocampal pyramidal cells, interneurons, and astrocytes
[3, 24, 75, 76, 94, 131]. Presently, it is unclear how the
activation of both mAC hRs and nAChRs, working in con-
cert, can modulate the oscillatory properties of neurons
within the hippocampus. Understanding how cholinergic
receptor signaling regul ates hippocampal network activity
is critical since dy sregulation of normal oscillations may
induce seizures [11, 27, 123], and cognitive deficits linked
with AD [39].
Structurefunction aspects of nAChRs and related
cys-loop receptor proteins
The focus of my lab has been on understanding the proper-
ties of nAChRs in the rodent hippocampus, the activation of
which is thought to be involved in regulatin g excitability,
plasticity, and cognitive function [59, 67, 78, 100]. Thus far,
at least nine different nAChR subunits are known to be
expressed in rodent brain, resulting in multiple functional
subtypes of nAChRs. In the hippocampus, the most preva-
lent subtypes of functional nAChR s that are expressed are
comprised of the a7 and a4β2 subtypes [1, 2, 68, 71 , 103,
116, 127]. The neuronal nAChR s are known to be differen-
tially permeable to calcium [ 9 , 21, 43, 105]. For example,
activation of the a7-containing (but not the non-a7)
nAChRs will elicit local changes in cytoplasmic calcium
levels in interneurons [35, 36, 70] and astrocytes [107 , 110,
126], and it is this calcium influx that is though t to underlie
theroleofa7 nAChRs in synaptic plasticity and mem-
ory processes. However, this influx of calcium can also
have deleterious consequences by inducing neurotoxicity
[44, 85, 96].
The nAChRs are in the superfamily of cys-loop receptors
(Fig. 1), which also includes the acetylcholine-binding pro-
teins (AChBPs), a solub le protein from mollusks and the
marine annelid Capitella teleta [17, 91] that is analogous to
the extracellular ligand-binding domain of the cys-loop
receptors. The binding of ACh to the extracellular interface
between two nAChR subunits induces channel opening [51]
(Fig. 1). While the precise steps between ligand binding and
channel gating are presently unknown, the Auerbach Lab
has provided some of the most complete data and models on
the stepwise interactions that may be occurring from ligand
binding to channel gating in the adult-type mouse muscle
nAChR. As recently reported [64], they are proposing a
mechanism similar to that of glutamate ligand-gated ion
channels whereby after the diffusion of agonist to the bind-
ing site (docking), the binding states undergo two confor-
mational changes (catch and hold). The first conformational
Transmembrane
Domain
M2-M3 linker
Cys-loop
1- 2 linker
C-loop
10-M1 linker
8- 9 linker
8- 9 linker
Cys-loop
Ligand Binding
Domain
ββ
ββ
β
ββ
Fig. 1 Molecular model of the rat a7 nAChR with ligand-binding
domain. A side view of the pentameric a7 receptor model is shown on
the left.Thea-helices are shown in red and the β-strands in blue.
The extracellular ligand-binding domain is shown up close on the
right. The ligand-bindin g site is composed of a cluster of aromatic
residues from both the principal and complementary subunits and
is capped by t he C-lo op. Th e t ransitio n domai n con sists of several
loopsasshown
442 Pflugers Arch - Eur J Physiol (2013) 465:441450
Page 2

You are reading a preview. Would you like to access the full-text?

Page 10
  • Source
    • "We will not analyze in detail the extensive issue of the direct regulation of the CNS by nAChRs, which is not central to our discussion. We refer the interested reader to two recent reviews on the topic [82, 84] , as well as on other chapters of the present issue. "
    [Show abstract] [Hide abstract] ABSTRACT: The interaction between the immune system and the central nervous system is largely unknown and under intense scrutiny by the biomedical community. Research results during the last decades have identified important two-way communication processes between these two systems, mediated by the cytokine network as well as by “classical” neurotransmitters. The dogma of a separate functioning of the two systems has been conclusively challenged with the discovery that not only neurotransmitters affect immune system function, but also inflammation affects neuronal cells through the same “cytokine network” that connects the different components of the immune system. The “classical” transmitter acetylcholine is an important modulator of both neuronal and immune function through both muscarinic and nicotinic receptors. Among the latter, α7 nicotinic acetylcholine receptors (nAChRs) possess the peculiar property of being expressed in immune cells as well as in neurons. While the modulation of neuronal activity by direct activation of α7 nAChRs is relatively well described, the hypothesis that α7 nAChRs may influence neuronal behavior indirectly, through inhibition of inflammation, is a relatively new concept. This review aims to summarize the evidence that activation of α7 nAChRs may influence brain function not only by direct action on certain neuronal pathways, but also by reducing inflammation (central and/or peripheral), decreasing the levels of circulating cytokines and consequently, their influence on neuronal activity.
    Full-text · Article · Apr 2016
  • Source
    • "It is well recognised that a7 nAChRs can regulate both excitatory and inhibitory signalling in the brain (Griguoli and Cherubini, 2012; Yakel, 2013; Hedrick and Waters, 2015). In the PFC, layer V pyramidal neurons are excited by nAChRs that enhance glutamatergic inputs (hitherto attributed to b2* nAChRs (Lambe et al., 2003)) and nAChRs also increase inhibition to layer V pyramidal neurons (Couey et al., 2007 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Cognitive and attentional processes governed by the prefrontal cortex (PFC) are influenced by cholinergic innervation. Here we have explored the role of α7 nicotinic acetylcholine receptors (nAChRs) as mediators of cholinergic signalling in the dorsomedial (prelimbic) PFC, using mouse brain slice electrophysiology. Activation of α7 nAChRs located on glutamatergic terminals and cell soma of GABAergic interneurons increased excitation and inhibition, respectively, in layer V of the prelimbic cortex. These actions were distinguished by their differential dependence on local acetylcholine (ACh): potentiation of endogenous cholinergic signalling with the positive allosteric modulator, PNU-120596, enhanced spontaneous excitatory events, an effect that was further increased by inhibition of acetylcholinesterase. In contrast, α7 nicotinic modulation of inhibitory signalling required addition of exogenous agonist (PNU-282987) as well as PNU-120596, and was unaffected by acetylcholinesterase inhibition. Thus α7 nAChRs can bi-directionally regulate network activity in the prelimbic cortex, depending on the magnitude and localisation of cholinergic signalling. This bidirectional influence is manifest in dual effects of α7 nAChRs on theta-burst-induced long-term potentiation (LTP) in layer V of the prelimbic cortex. Antagonism of α7 nAChRs significantly decreased LTP implicating a contribution from endogenous ACh, consistent with the ability of local ACh to enhance glutamatergic signalling. Exogenous agonist plus potentiator also decreased LTP, indicative of the influence of this drug combination on inhibitory signalling. Thus α7 nAChRs make a complex contribution to network activity and synaptic plasticity in the prelimbic cortex.
    Full-text · Article · Feb 2016 · Neuropharmacology
  • Source
    • "In the brain, nAChRs are ligand-gated ion channels permeable to cations, including Ca 21 , that produce membrane depolarization and postsynaptic excitation or stimulation of neurotransmitter release (Dani and Bertrand, 2007). nAChRs comprise nine different subunits (a 2–7 and ß 2–4 ) that combine as either homomeric or heteromeric pentameric receptors (Dani and Bertrand, 2007; Yakel, 2013). The homomeric a 7 and the heteromeric a 4 ß 2 are the two major subtypes of nAChRs found in the mammalian brain (Gotti et al., 2009 ); they have previously been found to be expressed in the BLA (Hill et al., 1993; Seguela et al., 1993 ) and appear to regulate neuronal excitability by presynaptically modulating neurotransmitter release or directly regulating neuronal activity by their position on somatodendritic sites of interneurons or principal neurons (Klein and Yakel, 2006; Pidoplichko et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of γ-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, an alteration in GABAA receptor activation, or a dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or development of seizure activity. This Review discusses the anatomy, development, and physiology of the GABAergic system in the BLA and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid-sensing ion channel 1a, cannabinoid receptor 1, and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affect inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/fragile X syndrome) and neurodegenerative (Alzheimer's disease) diseases and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2015 · Journal of Neuroscience Research
Show more