Module 10: Neuronal Signalling

Aging is considered a contributing factor to many diseases such as cardiovascular disease, Alzheimer’s disease, and hearing loss. Age-related hearing loss, also termed presbycusis, is one of the most common sensory impairments worldwide, affecting one in five people over 50 years of age, and this prevalence is growing annually. Associations have emerged between presbycusis and detrimental health outcomes, including social isolation and mental health. It remains largely untreatable apart from hearing aids, and with no globally established prevention strategies in the clinical setting. Hence, this review aims to explore the pathophysiology of presbycusis and potential therapies, based on a recent advancement in bile acid-based bio-nanotechnologies. A comprehensive online search was carried out using the following keywords: presbycusis, drugs, hearing loss, bile acids, nanotechnology, and more than 150 publications were considered directly relevant. Evidence of the multifaceted oxidative stress and chronic inflammation involvement in cellular damage and apoptosis that is associated with a loss of hair cells, damaged and inflamed stria vascularis, and neuronal signalling loss and apoptosis continues to emerge. New robust and effective therapies require drug delivery deeper into the various layers of the cochlea. Bile acid-based nanotechnology has gained wide interest in its permeation-enhancing ability and potential for numerous applications in treating presbycusis.

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Neurobiology of phenotypic plasticity in the light of climate change

Neuroforum ◽

10.1515/nf-2021-0029 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Linda C. Weiss

Keyword(s):

Climate Change ◽

Phenotypic Plasticity ◽

Sensory Systems ◽

Chemical Information ◽

Adaptive Potential ◽

Worst Case ◽

Changing Environments ◽

Neuronal Signalling ◽

Physiological Adaptations ◽

Signalling Cascade

Abstract Phenotypic plasticity describes the ability of an organism with a given genotype to respond to changing environmental conditions through the adaptation of the phenotype. Phenotypic plasticity is a widespread means of adaptation, allowing organisms to optimize fitness levels in changing environments. A core prerequisite for adaptive predictive plasticity is the existence of reliable cues, i.e. accurate environmental information about future selection on the expressed plastic phenotype. Furthermore, organisms need the capacity to detect and interpret such cues, relying on specific sensory signalling and neuronal cascades. Subsequent neurohormonal changes lead to the transformation of phenotype A into phenotype B. Each of these activities is critical for survival. Consequently, anything that could impair an animal’s ability to perceive important chemical information could have significant ecological ramifications. Climate change and other human stressors can act on individual or all of the components of this signalling cascade. In consequence, organisms could lose their adaptive potential, or in the worst case, even become maladapted. Therefore, it is key to understand the sensory systems, the neurobiology and the physiological adaptations that mediate organisms’ interactions with their environment. It is, thus, pivotal to predict the ecosystem-wide effects of global human forcing. This review summarizes current insights on how climate change affects phenotypic plasticity, focussing on how associated stressors change the signalling agents, the sensory systems, receptor responses and neuronal signalling cascades, thereby, impairing phenotypic adaptations.

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Binding of Gd3+to the neuronal signalling protein calexcitin identifies an exchangeable Ca2+-binding site

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x16003526 ◽

2016 ◽

Vol 72 (4) ◽

pp. 276-281

Author(s):

Lucas Chataigner ◽

Jingxu Guo ◽

Peter T. Erskine ◽

Alun R. Coker ◽

Steve P. Wood ◽

...

Keyword(s):

Metal Ions ◽

Binding Site ◽

Metal Binding ◽

Calcium Signalling ◽

Specific Protein ◽

Metal Binding Sites ◽

Calcium Sensing ◽

Neuronal Signalling ◽

Ef Hand ◽

Ef Hands

Calexcitin was first identified in the marine snailHermissenda crassicornisas a neuronal-specific protein that becomes upregulated and phosphorylated in associative learning. Calexcitin possesses four EF-hand motifs, but only the first three (EF-1 to EF-3) are involved in binding metal ions. Past work has indicated that under physiological conditions EF-1 and EF-2 bind Mg2+and Ca2+, while EF-3 is likely to bind only Ca2+. The fourth EF-hand is nonfunctional owing to a lack of key metal-binding residues. The aim of this study was to use a crystallographic approach to determine which of the three metal-binding sites of calexcitin is most readily replaced by exogenous metal ions, potentially shedding light on which of the EF-hands play a `sensory' role in neuronal calcium signalling. By co-crystallizing recombinant calexcitin with equimolar Gd3+in the presence of trace Ca2+, EF-1 was shown to become fully occupied by Gd3+ions, while the other two sites remain fully occupied by Ca2+. The structure of the Gd3+–calexcitin complex has been refined to anRfactor of 21.5% and anRfreeof 30.4% at 2.2 Å resolution. These findings suggest that EF-1 of calexcitin is the Ca2+-binding site with the lowest selectivity for Ca2+, and the implications of this finding for calcium sensing in neuronal signalling pathways are discussed.

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Transcriptomic analysis reveals a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles

10.1101/2022.01.13.476286 ◽

2022 ◽

Author(s):

Emily Robb ◽

Erin McCammick ◽

Duncan Wells ◽

Paul McVeigh ◽

Erica Gardiner ◽

...

Keyword(s):

Nervous System ◽

Rapid Growth ◽

Growth And Development ◽

Liver Fluke ◽

Fasciola Hepatica ◽

Expression Profiles ◽

Neuronal Signalling ◽

Growth Development

Fasciola spp. liver fluke have significant impacts in veterinary and human medicine. The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides. Functional genomic approaches underpinned by in vitro culture of juvenile Fasciola hepatica facilitate control target validation in the most pathogenic life stage. Comparative transcriptomics of in vitro and in vivo maintained 21 day old F. hepatica finds that 86% of genes are expressed at similar levels across maintenance treatments suggesting commonality in core biological functioning within these juveniles. Phenotypic comparisons revealed higher cell proliferation and growth rates in the in vivo juveniles compared to their in vitro counterparts. These phenotypic differences were consistent with the upregulation of neoblast-like stem cell and cell-cycle associated genes in in vivo maintained worms. The more rapid growth/development of in vivo juveniles was further evidenced by a switch in cathepsin protease expression profiles, dominated by cathepsin B in in vitro juveniles and then by cathepsin L in in vivo juveniles. Coincident with more rapid growth/development was the marked downregulation of both classical and peptidergic neuronal signalling components in in vivo maintained juveniles, supporting a role for the nervous system in regulating liver fluke growth and development. Differences in the miRNA complements of in vivo and in vitro juveniles identified 31 differentially expressed miRNAs, notably fhe-let-7a-5p , fhe-mir-124-3p and, miRNAs predicted to target Wnt-signalling, supporting a key role for miRNAs in driving the growth/developmental differences in the in vitro and in vivo maintained juvenile liver fluke. Widespread differences in the expression of neuronal genes in juvenile fluke grown in vitro and in vivo expose significant interplay between neuronal signalling and the rate of growth/development, encouraging consideration of neuronal targets in efforts to dysregulate growth/development for parasite control.

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Optogenetic Analysis of Area‐Specific Glial‐Neuronal Signalling

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1064.19 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Feige Tang ◽

Melina F. Figueiredo ◽

Alex V Gourine ◽

Anja G Teschemacher ◽

Sergey Kasparov

Keyword(s):

Neuronal Signalling

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Taenia larvae possess distinct acetylcholinesterase profiles with implications for host cholinergic signalling

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0008966 ◽

2020 ◽

Vol 14 (12) ◽

pp. e0008966

Author(s):

Anja de Lange ◽

Ulrich Fabien Prodjinotho ◽

Hayley Tomes ◽

Jana Hagen ◽

Brittany-Amber Jacobs ◽

...

Keyword(s):

Membrane Surface ◽

Taenia Solium ◽

Acetylcholinesterase Activity ◽

Bioinformatic Analysis ◽

Functional Protein ◽

Taenia Crassiceps ◽

Human Sequence ◽

Neuronal Signalling ◽

Whole Cell Patch Clamp ◽

Acquired Epilepsy

Larvae of the cestodes Taenia solium and Taenia crassiceps infect the central nervous system of humans. Taenia solium larvae in the brain cause neurocysticercosis, the leading cause of adult-acquired epilepsy worldwide. Relatively little is understood about how cestode-derived products modulate host neural and immune signalling. Acetylcholinesterases, a class of enzyme that breaks down acetylcholine, are produced by a host of parasitic worms to aid their survival in the host. Acetylcholine is an important signalling molecule in both the human nervous and immune systems, with powerful modulatory effects on the excitability of cortical networks. Therefore, it is important to establish whether cestode derived acetylcholinesterases may alter host neuronal cholinergic signalling. Here we make use of multiple techniques to profile acetylcholinesterase activity in different extracts of both Taenia crassiceps and Taenia solium larvae. We find that the larvae of both species contain substantial acetylcholinesterase activity. However, acetylcholinesterase activity is lower in Taenia solium as compared to Taenia crassiceps larvae. Further, whilst we observed acetylcholinesterase activity in all fractions of Taenia crassiceps larvae, including on the membrane surface and in the excreted/secreted extracts, we could not identify acetylcholinesterases on the membrane surface or in the excreted/secreted extracts of Taenia solium larvae. Bioinformatic analysis revealed conservation of the functional protein domains in the Taenia solium acetylcholinesterases, when compared to the homologous human sequence. Finally, using whole-cell patch clamp recordings in rat hippocampal brain slice cultures, we demonstrate that Taenia larval derived acetylcholinesterases can break down acetylcholine at a concentration which induces changes in neuronal signalling. Together, these findings highlight the possibility that Taenia larval acetylcholinesterases can interfere with cholinergic signalling in the host, potentially contributing to pathogenesis in neurocysticercosis.

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