Nicotinic receptor function: new perspectives from knockout mice

doi:10.1016/S0165-6147(00)01489-9

Trends in Pharmacological Sciences

Volume 21, Issue 6, 1 June 2000, Pages 211-217

https://doi.org/10.1016/S0165-6147(00)01489-9 Get rights and content

Abstract

Knockout mice, in which one or more genes of interest are silenced, provide unique opportunities to analyse diverse aspects of gene function in vivo. In particular, the contribution of the encoded protein(s) in complex behaviours can be assessed. Since the first targeted disruption in 1995 of the gene encoding the β2-subunit of the nicotinic acetylcholine receptor (nAChR), all but a few of the mammalian nAChR subunits have been disrupted (i.e. α7, α4, α3, α9, β4 and β3). Recent advances brought by genetically modified mice to our understanding of the endogenous composition and role of nAChRs in the nervous system, and of the diverse pharmacological actions of nicotine regarding learning, analgesia, reinforcement, development and aging in the brain will be discussed.

Section snippets

Pharmacology and subunit composition

Equilibrium binding studies have distinguished two main categories of nAChR pentamers in the brain on the basis of their high affinity for either nicotine or α-bungarotoxin (α-BgT). The former are considered to be formed by α4- and β2-subunit-containing nAChRs (or α4β2*-nAChRs, following recommended nomenclature¹¹) and the latter are thought to be α7- or α7*-nAChRs. Alkondon and Albuquerque have compared agonist (such as nicotine, cytisine and choline) and antagonist (such as α-BgT) potencies,

Behavioural analysis: endogenous functions of ACh

CNS nuclei with ACh-containing neurones (such as the pedunculopontine nucleus, medial septal nucleus and nucleus basalis) send widespread projections to most areas in the brain. Moreover, human disorders with symptomatic cognitive impairments linked to abnormalities of the neurotransmitter system for ACh, as well as a wealth of animal experiments, support a role of this system in learning and memory mediated through nAChRs (1, 19). In addition, the principal synaptic transmission in autonomic

Behavioural analysis: nicotine-elicited responses

KO mice have been instrumental in unravelling the specific contribution of individual nAChR subunits to the multiple pharmacological actions of nicotine on behaviour.

Development, neurodegeneration and aging

Impairments in ACh-mediated transmission take place both in normal aging and in age-related neurodegenerative diseases². Given that nicotine exhibits a neuroprotective effect on cultured cells, it has been proposed that deficits in nAChRs-mediated transmission contribute directly to the alteration of brain tissue observed in these normal or pathological conditions. Moreover, the presence of ACh-releasing circuits in embryonic neural tissue suggests a role for ACh and nAChRs during development²⁶.

Concluding remarks

KO mice have confirmed most and invalidated some of the previous ideas of the subunit composition of functional receptors, and the role these receptors have in development and aging. Using these mice, a contribution of nAChRs to survival has been demonstrated in the PNS, and an endogenous role for nAChRs in learning has been revealed in the CNS. Developmental compensatory mechanisms might mask adult physiological or behavioural differences resulting from the absence of an endogenous nAChR

Acknowledgements

The authors are indebted to Dr Michele Zoli for critical reading of the manuscript. The authors’ research was supported by grants from the Collège de France, the Association Française contre les Myopathies, Reynolds Pharm., EEC Biotech and Biomed Programs (960236 and BMH1-CT-94-1060), and The National Alliance for Research on Schizophrenia and Depression.

Glossary

Chemical name

ABT594:: (R)-5-(2-azetidinyl-methoxy)-2-chloropyridine

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Citation Excerpt :
Nicotinic acetylcholine receptors (nAChRs) are a class of ligand gated ion channels located throughout the central and peripheral nervous system that are composed of five subunits with seventeen identified subunit combinations [1–4].
The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits.
Differential α4(+)/(-)β2 agonist-binding site contributions to α4β2 nicotinic acetylcholine receptor function within and between isoforms
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Trends in Pharmacological Sciences

ReviewNicotinic receptor function: new perspectives from knockout mice

Abstract

Section snippets

Pharmacology and subunit composition

Behavioural analysis: endogenous functions of ACh

Behavioural analysis: nicotine-elicited responses

Development, neurodegeneration and aging

Concluding remarks

Acknowledgements

Glossary

Chemical name

EMBO J

J. Pharmacol. Exp. Ther.

Pharmacol. Toxicol

Proc. Natl. Acad. Sci. U. S. A

Proc. Natl. Acad. Sci. U. S. A

Nicotinic systems and cognitive function

Psychopharmacology

Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor

Proc. Natl. Acad. Sci. U. S. A

Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

Nature

Mice heterozygous for the α7 L250T nicotinic acetylcholine receptor mutation show a partial gain of function for this receptor

Soc. Neurosci. Abstr

Role of α9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation

Neuron

Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain

Nature

Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine

Nature

Multiorgan autonomic dysfunction in mice lacking the β2 and the β4 subunits of neuronal nicotinic acetylcholine receptors

J. Neurosci

Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits

Pharmacol Rev

Identification of four classes of brain nicotinic receptors using β2 mutant mice

J. Neurosci

Knock-out animals as models for studying nAChR function

Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents

J. Neurosci

Review
Nicotinic receptor function: new perspectives from knockout mice