Preface: Cholinergic Mechanisms

This special issue is a companion to the meeting ‘XVth International Symposium on Cholinergic Mechanisms’, and is edited by Israel Silman, Marco Prado and Pascale Marchot. In the review articles, renowned researchers in the field capture key mechanisms of cholinergic neurotransmission, from genomic amplification of cholinesterase genes, splicing and post-translational modifications; features of the neuromuscular junction, implications of cholinergic circuitry that are relevant to addiction, anxiety and mood, to preclinical models, protein biomarkers, and clinical findings that are relevant to pathology, for example, developmental neurotoxicity. The broad variety of features reflects the impact of cholinergic mechanisms on many physiological events and emphasizes the importance of research in this area. This is the Preface for the special issue XVth International Symposium on Cholinergic Mechanisms. Acetylcholine (ACh) was identified by Sir Henry Dale in 1914-15, but it was Otto Loewi who first demonstrated its role as a chemical messenger or neurotransmitter. Cholinergic neurons, which have the ability to synthesize, release and metabolize ACh, are the predominant neurons in the autonomic nervous system and the voluntary motor system. In the brain, cholinergic neurons form several nuclei that project to long distances, innervating almost all brain regions (Fig. 1). In the striatum, and possibly also in the cortex and the hippocampus, there are populations of cholinergic interneurons whose functional roles are still poorly understood. Knowledge of cholinergic signaling in both the periphery and the brain has been the subject of intensive research, accompanied by great progress, especially in recent years. This is largely because of the association of cholinergic transmission with a sizeable number of neurological diseases in both the central and peripheral nervous systems, but also because a broad repertoire of natural toxins and synthetic compounds target one or other of the components of the cholinergic synapse. This immense amount of information encompasses the mechanisms of ACh synthesis, storage and degradation and of its actions on the multiple subtypes of muscarinic and nicotinic receptors. Progress in dissecting cholinergic function in the most recent years is reviewed in this special issue on Cholinergic Mechanisms, based on the successful XVth International Symposium on Cholinergic Mechanisms (XVth ISCM) held in Marseille in October 2016, which was opened with a lecture by Jean-Pierre Changeux. This symposium was the most recent in a series of meetings, the first of which was organized in 1974 by the late Edith Heilbronn, in Skokloster, Sweden. One of those present at the first meeting was Alex Karczmar (who is now just 100 years old). Although unable to attend this time, he served as President of the International Advisory Board of the ISCM until 2013. Hermona Soreq then succeeded him as President, but he remains an active and energetic Permanent Honorary President. The fundamental research presented during the ISCMs ranges from such topics as structure/function relationships in such proteins as the cholinesterases and acetylcholine receptors, and their biosynthesis and assembly, through mechanisms of neurotransmitter release, the ultrastructure of cholinergic synapses in the central and peripheral nervous system, and on to developmental, neuroanatomical and functional aspects of cholinergic circuits. At the applied level, these meetings address such cogent themes as the design and mechanisms of action of insecticides, prophylaxis and treatment of nerve agent intoxication, peripheral neurological diseases such as myasthenia gravis, cholinergic aspects of Alzheimer's disease, schizophrenia, autism spectrum diseases and the complex pharmacology of nicotine addiction. The molecular, electrophysiological and functional knowledge of the cholinergic neuromuscular synapse (reviewed herein by Legay and Mei 2017) has long served, and continues to serve, as a fundamental paradigm for understanding all types of chemical synapses in the periphery, the spinal cord and the brain. Functional diversity and assembly of the human neuromuscular junction depends, at least in part, on exquisite regulation of mRNA metabolism by alternative splicing. An insightful view of RNA-binding proteins and genes at the neuromuscular junction that undergo alternative splicing is provided by Ohno et al. (2017). Both developmental regulation and aberrant splicing in diseases is discussed. Diseases of the neuromuscular junction are often devastating. New animal models to study motor paralysis and regeneration of the neuromuscular junction are elegantly reviewed by Rigoni and Montecucco (2017). The ability to achieve regeneration of motor axons is still a major goal for scientists studying motor terminals, and enhanced understanding of the factors controlling it will have important consequences for the treatment of a number of diseases. An important discovery that has triggered considerable interest in recent years is the evidence presented that certain non-neuronal tissues can synthesize, store and secrete ACh (Wessler and Kirkpatrick 2008). This, in turn, has led to the demonstration that non-neuronal ACh can regulate the cholinergic anti-inflammatory response (Rosas-Ballina et al. 2011), insulin secretion (Rodriguez-Diaz et al. 2011) and cardiac function (Roy et al. 2013, 2016). Non-neuronal ACh secretion is a potential ancient form of cellular communication, and its impact on reproduction in such insects as honeybees may underlie changes in biodiversity as a result of insecticide use, an issue reviewed in detail by Wessler and Kirkpatrick (2017). The fundamental role played by acetylcholinesterase in modulating cholinergic tone has received particular attention in recent years. The elegant mechanisms of acetylcholinesterase biosynthesis and trafficking are reviewed in detail by Richard Rotundo (Rotundo 2017). Recent insights into structure/function relationships in this important pharmacotoxicological target are surveyed by Silman and Sussman (2017). Given that acetylcholinesterase is an important target for some of the most toxic chemicals, such as organophosphorous nerve agents, understanding mechanisms for their reactivation is of medical importance. This timely topic, given the recent use of the nerve agent sarin in Syria, is reviewed in detail by Masson and Nachon (2017). This is followed by a review of developmental consequences of exposure to pesticides that inhibit cholinesterases by Albuquerque and colleagues (Albuquerque et al. 2017). Genomic regulation of cholinesterase and gene amplification are discussed by Chatonnet and collaborators (Chatonnet et al. 2017), providing important insights into physiological and evolutional roles of gene amplification. Genomic regulation, miRNAs regulating cholinergic activity and single nucleotide polymorphisms that control cholinergic tone in humans are topics elegantly discussed by Simchovitz et al. (2017), providing ‘state-of-the-art’ insights into cholinergic aspects of personalized medicine. Toxins that impact the function of cholinergic activities have long provided tools for obtaining mechanistic information on the roles played by cholinergic receptors, acetylcholinesterase and presynaptic elements involved in ACh release. Evolution has selected numerous toxins, either peptidic or organic, that target the cholinergic system. New insight into such pharmacological tools as the three-finger toxins found in the venoms of Elapidae snakes, whose common structural motif triggers diversified receptor specificities, are reviewed by Kessler et al. (2017). The structure-function relationships of macrocyclic imine toxins that target nicotinic receptors are discussed in detail by Molgo et al. (2017). These toxins from dinoflagellates accumulate in mollusks and have an important impact on the shellfish food industry. Nicotinic receptors were a highlight of the meeting, discussed by Jean-Pierre Changeux along with the presentation on the first structure of a nicotinic acetylcholine receptor at atomic resolution, that of the human α4β2 nicotinic receptor (Morales-Perez et al. 2016), following the recent publications of the structure of G-coupled muscarinic receptors (Haga et al. 2012; Kruse et al. 2012, 2014a,b; Thal et al. 2016). The role of cholinergic signaling in the medial habenula and interpeduncular nucleus in addiction and anxiety are reviewed by John Dani and colleagues (McLaughlin et al., 2017). Identification of the circuits involved in spinal central pattern generators (CPGs) is important for understanding neural control of movement and developing novel approaches to treatment of spinal cord injury patients. Anglister et al. (2017) review this topic, and present a model describing how ascending sacro-lumbar connectivity is involved in modulation of locomotor rhythm by sacral cholinergic components. The use of peripheral biomarkers, including nicotinic receptor subunit expression in granulocytes, as a proxy for following chronic nicotinic exposure, was covered by Mulcahy and Lester (2017). Several groups of cholinergic neurons play important roles in addiction and in neurodegenerative diseases. Cholinergic neurons can secrete other neurotransmitters, and an overview of cholinergic/glutamatergic neurotransmission in the striatum and their impact in addiction and Parkinson's disease is provided by Kljakic et al. (2017). Cholinergic signaling regulates learning and memory, and this process is severely disturbed in Alzheimer's disease and other forms of dementia. Recent neuroimaging (Teipel et al. 2014; Schmitz and Nathan Spreng 2016) and epidemiological data (Gray et al. 2015; Risacher et al. 2016) have led to a resurgence in understanding the role played by cholinergic signaling in dementia. Lorna Role provided examples of using optogenetic approaches to interrogate cholinergic signaling in fear (see manuscript in this special issue by López-Hernández et al. 2017). Finally, novel insights into how cholinergic signaling regulates cognition are provided in a comprehensive review of the cholinergic regulation of hippocampal function by Haam and Yakel (2017). The physiology of cholinergic signaling is a broad topic, to say the least, and ACh can regulate almost all systems in the human body. This special issue of the Journal of Neurochemistry provides a cross-section through this diversity by including 19 Mini-Reviews that survey the ‘state-of-the-art’ in a wide range of the topics covered by the XVth ISCM, along with the abstracts of 94 of the presentations made at the meeting. Marco Prado is an editor with the Journal of Neurochemistry. The authors declare no further conflicts of interest.

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