Neuronal signaling最新文献

The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer's disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer's research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.

Axonal transport is the essential process by which neurons actively traffic a variety of cargoes between the cell soma and axon terminals. Accordingly, dysfunctional axonal transport is linked to many nervous system conditions. Therefore, being able to image and quantify this dynamic process in live neurons of animal disease models is beneficial for understanding neuropathology and testing new therapies at the preclinical level. As such, intravital approaches have been developed to assess cargo movement in the hindlimb sciatic nerves of live, anaesthetised mice. Here, we describe an adapted method for in vivo imaging of axonal transport in intact median and ulnar nerves of the rodent forelimb. Injection of a fluorescently labelled and non-toxic fragment of tetanus neurotoxin (H_CT) into the mouse forepaw permits the identification of signalling endosomes in intact axons of median and ulnar nerves. Through immunofluorescent analysis of forelimb lumbrical muscles and median/ulnar nerves, we confirmed that H_CT is taken up at motor nerve terminals and predominantly locates to motor axons. We then showed that the baseline trafficking of signalling endosomes is similar between the median/ulnar nerves and the sciatic nerve in adult wild-type mice. Importantly, this adapted method can be readily tailored for assessment of additional cargoes, such as mitochondria. By measuring transport in forelimb and hindlimb nerves, comparative anatomical and functional analyses can be performed in rodent disease models to aid our understanding of peripheral nerve disease pathogenesis and response to injury.

This themed collection celebrates 125 years of the synapse through a series of reviews written by a team of international experts in the field. The first in the series explains Sherrington's contribution to the debate about the term 'synapse' and its function in neuronal signaling. The topics that follow cover recent developments in a wide range of topics: new technologies for research of synaptic structure; proteomics and the regulation of synaptic integrity and function; their role in the processing of information in thalamic neuronal circuits; and how genetic mutations can modify synaptic function in ways that can have profound effects on mood, cognition and behaviour.

The thalamus plays a pivotal role in the integration and processing of sensory, motor, and cognitive information. It is therefore important to understand how the thalamus operates in states of both health and disease. In the present review, we discuss the function of the Group II metabotropic glutamate (mGlu) receptors within thalamic circuitry, and how they may represent therapeutic targets in treating disease states associated with thalamic dysfunction.

This themed collection of articles was prompted by a collaboration between Neuronal Signaling and the British Neuroscience Association. The Biochemical Society and Portland Press organised a symposium at the BNA Festival of Neuroscience in 2021, focused on the development and use of experimental models of human neuronal disorders. One aspect dealt with how new technologies are being (or could be) used both as a substitute for, or to complement, research that uses whole animal models. Another aspect discussed factors that need to be considered when appraising the validity of animal models of complex, multifactorial neuronal disorders. Given its relevance to the scope of Neuronal Signaling, the journal's Editorial Board developed a themed collection of content around this symposium entitled Emerging technologies for research models of human neuronal disorders in vivo and in vitro. We were delighted that speakers from the symposium and other experts working in this field agreed to submit reviews for the collection, which offers an invaluable resource both for researchers who are already experts in this field and those who need merely to learn about its scope and potential.

Synapses are minuscule, intricate structures crucial for the correct communication between neurons. In the 125 years since the term synapse was first coined, we have advanced a long way when it comes to our understanding of how they work and what they do. Most of the fundamental discoveries have been invariably linked to advances in technology. However, due to their size, delicate structural integrity and their sheer number, our knowledge of synaptic biology has remained somewhat elusive and their role in neurodegenerative diseases still remains largely unknown. Here, we briefly discuss some of the imaging technologies used to study synapses and focus on the utility of the high-resolution imaging technique array tomography (AT). We introduce the AT technique and highlight some of the ways it is utilised with a particular focus on its power for analysing synaptic composition and pathology in human post-mortem tissue. We also discuss some of the benefits and drawbacks of techniques for imaging synapses and highlight some recent advances in the study of form and function by combining physiology and high-resolution synaptic imaging.

Synapses maintain their molecular composition, plasticity and function through the concerted action of protein synthesis and removal. The complex and polarized neuronal architecture poses specific challenges to the logistics of protein and organelle turnover since protein synthesis and degradation mainly happen in the cell soma. In addition, post-mitotic neurons accumulate damage over a lifetime, challenging neuronal degradative pathways and making them particularly susceptible to the effects of aging. This review will summarize the current knowledge on neuronal protein turnover mechanisms with a particular focus on the presynapse, including the proteasome, autophagy and the endolysosomal route and their roles in regulating presynaptic proteostasis and function. In addition, the author will discuss how physiological brain aging, which entails a progressive decline in cognitive functions, affects synapses and the degradative machinery.

This paper provides a review of some of the major historical developments in synaptic research and neurotransmission since the first appearance of the word 'synapsis' in 1895. The key contributions and inter-relationships of several significant scientists and Nobel Laureates, including Charles Sherrington, Henry Dale, Edgar Adrian and John Eccles are highlighted, and the influence of others such as John Langley and Thomas Elliott is stressed. A recurrent theme is the importance of language and the creation of new words.

Neurodevelopmental conditions (or neurodevelopmental disorders, NDDs) are highly heterogeneous with overlapping characteristics and shared genetic etiology. The large symptom variability and etiological heterogeneity have made it challenging to understand the biological mechanisms underpinning NDDs. To accommodate this individual variability, one approach is to move away from diagnostic criteria and focus on distinct dimensions with relevance to multiple NDDs. This domain approach is well suited to preclinical research, where genetically modified animal models can be used to link genetic variability to neurobiological mechanisms and behavioral traits. Genetic factors associated with NDDs can be grouped functionally into common biological pathways, with one prominent functional group being genes associated with the synapse. These include the neuroligins (Nlgns), a family of postsynaptic transmembrane proteins that are key modulators of synaptic function. Here, we review how research using Nlgn mouse models has provided insight into how synaptic proteins contribute to behavioral traits associated with NDDs. We focus on how mutations in different Nlgns affect social behaviors, as differences in social interaction and communication are a common feature of most NDDs. Importantly, mice carrying distinct mutations in Nlgns share some neurobiological and behavioral phenotypes with other synaptic gene mutations. Comparing the functional implications of mutations in multiple synaptic proteins is a first step towards identifying convergent neurobiological pathways in multiple brain regions and circuits.

Alzheimer's disease (AD) remains a major cause of morbidity and mortality worldwide, and despite extensive research, only a few drugs are available for management of the disease. One strategy has been to up-regulate cholinergic neurotransmission to improve cognitive function, but this approach has dose-limiting adverse effects. To avoid these adverse effects, new drugs that target specific receptor subtypes of the cholinergic system are needed, and the M1 subtype of muscarinic acetylcholine receptor (M1-mAChR) has been shown to be a good target for this approach. By using several strategies, M1-mAChR ligands have been developed and trialled in preclinical animal models and in human studies, with varying degrees of success. This article reviews the different approaches to targeting the M1-mAChR in AD and discusses the advantages and limitations of these strategies. The factors to consider in targeting the M1-mAChR in AD are also discussed.