Impaired Neurotransmission Research Articles

Adverse effects of polystyrene nanoplastic and its binary mixtures with nonylphenol on zebrafish nervous system: From oxidative stress to impaired neurotransmitter system

Micro(nano)plastics generally co-exist with other chemicals in the environment, resulting in inevitable interaction and combined toxic effects on biota. Nevertheless, little is known regarding the interaction of nanoplastics (NPs) with other co-occurring insults. Hereby, we investigated single and combined effects of chronic exposure (45 days) to polystyrene nanoplastic particulates (PS-NPs) and nonylphenol (4-NP) on zebrafish nervous system. Multiple biomarkers concerning with oxidative-stress [catalase (CAT) activity and reduced glutathione (GSH) level], cholinergic system [Acetylcholinesterase (AchE) activity], glutamatergic system [glutamine synthetase (GS) and glutamate dehydrogenase (GDH) activities], energy metabolism [a-ketoglutarate dehydrogenase (a-KGDH) activity], and histological alterations were assessed. Both single and binary exposure to PS-NPs and 4-NP induced oxidative stress through reducing CAT activity and GSH level, in which a more sever effect was noticed in combined exposure. The AchE activity was significantly inhibited only in single treatment groups demonstrating antagonistic interaction between PS-NPs and 4-NP. Effects on GS activity was also alleviated in binary exposure as compared with single exposure to each contaminant. In addition, an increase in GDH activity was noticed in PS-NPs at 10 and 100 μg/L, and simultaneous presence of PS-NPs and 4-NP with a greater response were observed in combined treatments. PS-NPs and 4-NP either in separate or binary mixtures disrupted energy metabolism by deficiency of α-KGDH activity; however, co-exposure to PS-NPs and 4-NP induced more intense adverse impacts on this parameter. Furthermore, histological analysis revealed that 4-NP and PS-NPs, alone or in combination, reduced neural cells. These findings provide new insight into the neurotoxic effects of binary exposure to PS-NPs and 4-NP at environmentally relevant concentrations. Overall, our findings raise concerns about the presence and toxicity of nano-scale plastic particulates and highlight the importance of investigating the interaction of Micro(nano)plastics with other environmental irritants.

N-Hydroxy-N-Propargylamide Derivatives of Ferulic Acid: Inhibitors of Cholinesterases and Monoamine Oxidases.

Alzheimer's disease (AD) is a complex disorder characterized by impaired neurotransmission in cholinergic and monoaminergic neurons, which, in combination with the accumulation of misfolded proteins and increased oxidative stress, leads to the typical features of the disease at the biomolecular level. Given the limited therapeutic success of approved drugs, it is imperative to explore rationally supported therapeutic approaches to combat this disease. The search for novel scaffolds that bind to different receptors and inhibit AD disease-related enzymes could lead to new therapeutic solutions. Here, we describe N-hydroxy-N-propargylamide hybrids 1-6, which were designed by combining the structures of Contilisant-a multifunctional anti-AD ligand-and ferulic acid, a natural antioxidant with various other biological activities. Among the synthesized compounds, we identified compound 4 as a micromolar inhibitor of hAChE with a potent radical-scavenging capacity comparable to resveratrol and Trolox. In addition, compound 4 chelated copper(II) ions associated with amyloid β pathology, mitochondrial dysfunction, and oxidative stress. The promising in vitro activity combined with favorable drug-like properties and predicted blood-brain barrier permeability make compound 4 a multifunctional ligand that merits further studies at the biochemical and cellular levels.

Biomarker Genes Discovery of Alzheimer's Disease by Multi-Omics-Based Gene Regulatory Network Construction of Microglia.

Microglia, the major immune cells in the brain, mediate neuroinflammation, increased oxidative stress, and impaired neurotransmission in Alzheimer’s disease (AD), in which most AD risk genes are highly expressed. In microglia, due to the limitations of current single-omics data analysis, risk genes, the regulatory mechanisms, the mechanisms of action of immune responses and the exploration of drug targets for AD immunotherapy are still unclear. Therefore, we proposed a method to integrate multi-omics data based on the construction of gene regulatory networks (GRN), by combining weighted gene co-expression network analysis (WGCNA) with single-cell regulatory network inference and clustering (SCENIC). This enables snRNA-seq data and bulkRNA-seq data to obtain data on the deeper intermolecular regulatory relationships, related genes, and the molecular mechanisms of immune-cell action. In our approach, not only were central transcription factors (TF) STAT3, CEBPB, SPI1, and regulatory mechanisms identified more accurately than with single-omics but also immunotherapy targeting central TFs to drugs was found to be significantly different between patients. Thus, in addition to providing new insights into the potential regulatory mechanisms and pathogenic genes of AD microglia, this approach can assist clinicians in making the most rational treatment plans for patients with different risks; it also has significant implications for identifying AD immunotherapy targets and targeting microglia-associated immune drugs.

DE-71 affected the cholinergic system and locomotor activity via disrupting calcium homeostasis in zebrafish larvae.

Polybrominated diphenyl ethers (PBDEs) can induce neurotoxicity, but the mechanism of their toxicity on the cholinergic system and locomotion behavior remains unclear. In this paper, zebrafish embryos were exposed to DE-71 (0, 1, 3, 10, 30, and 100µg/L) until 120h post fertilization, and its effects on the behavior and cholinergic system of zebrafish larvae and its possible mechanism were investigated. Results indicated a general locomotor activity impairment in the light-dark transition stimulation without affecting the secondary motoneurons. However, with the extension of test time in the dark or light, the decreased locomotor activity was diminished, a significant decrease only observed in the 100µg/L DE-71 exposure groups in the last 10min. Furthermore, whole-body acetylcholine (ACh) contents decreased after DE-71 exposure, whereas no changes in NO contents and inducible nitric oxide synthase activity were found. The expression of certain genes encoding calcium homeostasis proteins (e.g., grin1a, camk2a, and crebbpb) and the concentrations of calcium in zebrafish larvae were significantly decreased after DE-71 exposure. After co-exposure with calcium channel agonist (±)-BAY K8644, calcium concentrations, ACh contents, and locomotor activity in the light-dark transition stimulation was significantly increased compared with the same concentrations of DE-71 exposure alone, whereas no significant difference was observed compared with the control, indicating that calcium homeostasis is involved in the impairment of cholinergic neurotransmission and locomotor activity. Overall, our results suggested that DE-71 can impair the cholinergic system and locomotor activity by impairing calcium homeostasis. Our paper provides a better understanding of the neurotoxicity of PBDEs.

Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β.

The progression of neurodegenerative disorders can lead to impaired neurotransmission; however, the role of pathogenic factors associated with these diseases and their impact on the structures and functions of neurotransmitters have not been clearly established. Here we report the discovery that conformational and functional changes of a native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ) found as pathological factors in the brains of patients with Alzheimer's disease. These pathological elements induce the self-assembly of SST and, consequently, prevent it from binding to the receptor. In the reverse direction, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, attenuating their cytotoxicity and interactions with cell membranes. Our work demonstrates a loss of normal function of SST as a neurotransmitter and a gain of its modulative function against metal-Aβ under pathological conditions.

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74–88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.

Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice

Tetrahydrobiopterin (BH4) is a necessary cofactor for the synthesis of monoamines from essential amino-acids, phenylalanine, tyrosine and tryptophan. The BH4 synthesis pathway is induced by inflammatory factors but highly regulated processes maintain levels in a physiological range. However, BH4 activity can be durably altered in inflammation-related pathologies, such as certain types of depression, potentially involving impairment of dopaminergic neurotransmission. The purpose of this study was to investigate the response of the brain BH4 pathway to the inflammatory stimulus induced by lipopolysaccharide (LPS) in mice. Brain expression of genes related to BH4 synthesis, levels of BH4, changes in L-aromatic amino acid precursors of monoamines and dopamine levels were determined. As secondary aim, the effect of acute BH4 supply under the inflammatory challenge was tested on these parameters and on the expression of inflammatory cytokines. Mice were also submitted to the sucrose preference test and to the open-field in order to asses hedonic and locomotor responses to LPS, in addition to their modulation by BH4 supply. The LPS challenge resulted in decreased striatal DA levels and increased Phenylalanine/Tyrosine ratio, suggesting reduced BH4 activity. BH4 supply was effective to increase striatal BH4 levels, to restore the LPS-induced decreased in DA levels in striatum and to dampen the LPS-induced expression of inflammatory cytokines. At the behavioral level, BH4 supply was able to restore the loss of locomotor response to amphetamine in the LPS treated mice, suggesting a modulation of the dopaminergic neurotransmission.These data suggest that BH4 can be considered as a potential add-on molecule, helping to maintain or restore dopaminergic neurotransmission in neuroinflammatory conditions..

Glucose enrichment impair neurotransmission and induce Aβ oligomerization that cannot be reversed by manipulating O-β-GlcNAcylation in the C. elegans model of Alzheimer's disease

Amyloid beta (Aβ) plaques formation and impaired neurotransmission and neuronal behaviors are primary hallmarks of Alzheimer's disease (AD) that are further associated with impaired glucose metabolism in elderly AD's patients. However, the exact role of glucose metabolism on disease progression has not been elucidated yet. In this study, the effect of glucose on Aβ-mediated toxicity, neurotransmission and neuronal behaviors has been investigated using a C. elegans model system expressing human Aβ. In addition to regular diet, worms expressing Aβ were supplemented with different concentrations of glucose and glycerol and 5 mM 2-deoxyglucose to draw any conclusions. Addition of glucose to the growth medium delayed Aβ-associated paralysis, promoted abnormal body shapes and movement, unable to restore impaired acetylcholine neurotransmission, inhibited egg laying and hatching in pre-existing Aβ-mediated pathology. The harmful effects of glucose may associate with an increase in toxic Aβ oligomers and impaired neurotransmission. O-β-GlcNAcylation (O-GlcNAc), a well-known post-translational modification is directly associated with glucose metabolism and has been found to ameliorates the Aβ- toxicity. We reasoned that glucose addition might induce O-GlcNAc, thereby protect against Aβ. Contrary to our expectations, induced glucose levels were not protective. Increasing O-GlcNAc, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and, therefore, reduce Aβ- toxicity but not in the presence of high glucose. The effects of glucose cannot be effectively managed by manipulating O-GlcNAc in AD models of C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

0806 REM sleep without atonia in the Setting of Duchenne muscular dystrophy: Can it Serve a Protective Role?

Abstract Introduction Duchenne muscular dystrophy (DMD) has well-known associations with sleep-related breathing disorders such as sleep apnea and nocturnal hypoventilation. These disorders naturally follow from the progressive muscle weakness that is the hallmark of DMD. New data is emerging on the prevalence of other polysomnographic features affecting patients with DMD, particularly as they relate to the phenotype of the sleep disorders unique to DMD. We report on a patient with REM sleep without atonia (RWA) in DMD. Report of Cases: A 13-year-old male with DMD was referred for a polysomnogram (PSG) due to new-onset snoring, but there was no history to suggest dream enactment behavior. He was not taking any CNS-acting medication such as serotonergic or sedative-hypnotic medications. Neurologic examination was notable for diffuse symmetric muscle weakness requiring the use of a wheelchair. PSG revealed obstructive sleep apnea syndrome with an apnea-hypopnea index of 3/hr overall and 5/hr during REM sleep, a respiratory disturbance index of 9/hr with minimum O saturation of 84%, and evidence of RWA in three 30-second epochs meeting AASM scoring criteria. Dream-enactment behavior was absent during the PSG and historically. Conclusion We report on a previously unrecognized finding of RWA the setting of DMD. While sleep studies are routinely performed in DMD due to the significant association with sleep-disordered breathing and REM-related hypoventilation, the presence of RWA was unusual. The finding of RWA in the setting of a dystrophinopathy prompts important questions. While it is unlikely that RWA is an emerging sign of an ⍺-synucleinopathy in the setting of DMD, its presence in a young teenager raises the possibility of hypocretin deficiency in the setting of DMD, as is the case with myotonic dystrophy type 1 reflecting impaired hypocretin neurotransmission. However, a more attractive explanation is that RWA may promote a protective effect against sleep apnea in patients with vulnerability to REM-related hypoventilation. Our data suggest a potential protective role conferred by the preservation of muscle tone in the setting of sleep apnea in neuromuscular conditions. Support (If Any) None

The cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK.

The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including Wnt family morphogens. To investigate how these synaptic cues in NMJ development are transduced, particularly in the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane, we explored the function of Van Gogh-like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We found that conditional, muscle-specific ablation of Vangl2 in mice reproduced the NMJ differentiation defects seen in mice with global Vangl2 deletion. These alterations persisted into adulthood and led to NMJ disassembly, impaired neurotransmission, and deficits in motor function. Vangl2 and the muscle-specific receptor tyrosine kinase MuSK were functionally associated in Wnt signaling in the muscle. Vangl2 bound to and promoted the signaling activity of MuSK in response to Wnt11. The loss of Vangl2 impaired RhoA activation in cultured mouse myotubes and caused dispersed, rather than clustered, organization of AChRs at the postsynaptic or muscle cell side of NMJs in vivo. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and thus shed light on the molecular mechanisms underlying NMJ assembly.

Effects of the light-controlled nitric oxide donor “NORD-1” and light irradiation in rats with neurogenic erectile dysfunction

ABSTRACT Introduction Radical prostatectomy often causes erectile dysfunction (ED). This is considered to be due to surgery-induced nerve damage. Impairments in neurotransmission result in the release of nitric oxide (NO) in penile corpus cavernosum insufficiency. Therefore, phosphodiesterase-5 inhibitors are not necessarily effective for this type of ED. NO supplementation may be effective for this type of ED. However, NO acts on the whole body and thus may cause adverse effects. Recently, we have developed a light-controlled NO donor that enables spatially and temporally controlled NO release by light irradiation. Whether this type of NO donor is useful for neurogenic ED remains unknown. Objective We investigated whether this light-controlled NO donor “NORD-1” and light irradiation were effective for managing neurogenic ED in rats with bilateral cavernous nerve injury (BCNI). Methods We used eight-week-old male Wistar-ST rats. The rats were divided into four groups: Sham+SiR650 (control compound) (n=5), Sham+NORD-1 (n=5), BCNI+SiR650 (n=6), and BCNI+NORD-1 (n=6). Initially, sham or BCNI surgery was performed under anesthesia in each group. BCNI surgery was performed by crushing the bilateral cavernous nerves. Four weeks post-surgery, erectile function before and after the injection of each compound into the penile corpus cavernosum was evaluated based on the change in intracavernous pressure (ICP) under electrical stimulation of the cavernous nerve. The changes in ICP with and without light irradiation were also evaluated after the administration of each compound. Results Before administering each treatment without light irradiation, the ICP/mean arterial pressure (MAP) ratio under stimulation in the BCNI+SiR650 and BCNI+NORD-1 groups were lower than those in the Sham+SiR650 (P<0.01) and Sham+NORD-1 (P=0.06) groups. After the each treatment without light irradiation, the ICP/MAP ratio under stimulation in the Sham+NORD-1 group was slightly higher than that in the Sham+SiR650 group. However, the ICP/MAP ratio under stimulation in the BCNI+SiR650 and BCNI+NORD-1 groups remained significantly lower (P<0.05 and P<0.01, respectively). After the treatment with light irradiation, the ICP/MAP ratios under stimulation in the Sham+NORD-1 and BCNI+NORD-1 groups were significantly higher than those in the Sham+SiR650 (P<0.01) and BCNI+NORD-1 (P<0.01) groups, respectively. Conclusions The combination of NORD-1 and light irradiation may be useful for treating neurogenic ED, although its toxicity must be evaluated. Disclosure Work supported by industry: no.

Genomic Study of GABA Receptor Ligand Binding Sites of the Bivalve Mollusc Crassostrea virginica

GABA (γ‐aminobutyric acid) an inhibitory neurotransmitter in molluscs and other animals has not been well studied in bivalves. In humans, impairment of GABA neurotransmission can cause epilepsy. In the bivalve mollusc Crassostrea virginica, as well as other bivalves, serotonin is an excitatory neurotransmitter that increases beating rates of gill lateral cell cilia. Previously our lab demonstrated in C. virginica serotonin’s increase of cilia beating rates is blocked by applying GABA to the visceral or cerebral ganglia. Additionally, bicuculline methchloride, a GABAa receptor antagonist, blocked the effects of GABA. By using HPLC we previously detected GABA in low ng amounts in cerebral and visceral ganglia of C. virginica. Our immunofluorescence studies showed the presence of GABA neurons in cerebral and visceral ganglia; and that some serotonin neurons had GABA receptors on their soma. Recently the genome of C. virginica and other bivalves has begun to be mapped. By conducting BLAST searches of the NCBI (National Center for Biotechnology Information) database using DNA and protein sequences of C. virginica and other invertebrate and mammalian species we found matches for GABAa and GABAb receptor genes on C. virginicachromosomes 3 and 5, respectively. Various invertebrates had Percent Identity above 60%, while humans and mice had Percent Identity of about 40% to 50% for GABAa and GABAb. We hypothesize that the ligand binding sites (LBS) for GABAa and GABAb receptors in C. virginica are evolutionarily conserved and will closely match those of other animals. To study this, we conducted searches of the NCBI database for GABAa and GABAb LBS of C. virginica and compared them to other animals. We found GABAb LBS contained 4 amino acids (N, L, A, Y) in positions 34, 122, 123, 267 that were highly conserved in LBS of other bivalves, gastropods, insects, mice, rats and humans. GABAa LBS for C. virginica has not yet been identified. We did find LBS of other animals contained 2 amino acids (L, Y) that were highly conserved among the animals in which it has been identified. The C. virginica GABAa receptor does contain L and Y amino acids. The study complements our earlier physiology and cell biology studies demonstrating the presence and a function for GABA in C. virginica and shows the genome of C. virginica contains genes to produce GABA receptor LBS that are similar to those of other animals. This new information is valuable as it shows the simple nervous system of C. virginica can be used to conduct studies on GABA neurotransmission.

Thalamocortical Projections Are Significantly Impaired in the R6/2 Mouse Model of Huntington's Disease.

As Huntington’s disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL; motor) and ventral posteromedial nucleus (VPM; somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and wild-type (WT) mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared with WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting membrane potentials compared with WTs, cells in both nuclei displayed increased excitability in symptomatic, but not presymptomatic, R6/2 mice. Optical activation of VAL and VPM terminals elicited smaller magnitude current responses in cortical pyramidal neurons (CPNs) in both motor cortex (M1CTX) and somatosensory barrel cortex (BCTX) of symptomatic R6/2 mice compared with CPNs in WT mice. Furthermore, we observed a decrease in the frequency of thalamocortical excitatory quantal events in R6/2 BCTX CPNs, with no genotype-dependent differences in AMPA:NMDA response amplitude ratios. These data suggest there is a decrease in the transmission of thalamocortical information that is likely because of impaired neurotransmitter release.

Roles for Mitochondrial Complex I Subunits in Regulating Synaptic Transmission and Growth.

To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function and plasticity by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (300 Drosophila lines screened). From our screen, knockdown of a Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. We localized this neurotransmission function to the muscle. Pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns or pharmacological inhibition led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinson’s disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.

Development of a Novel Technique for the Measurement of Neuromuscular Junction Functionality in Isotonic Conditions

IntroductionThe neuromuscular junction (NMJ) is a chemical synapse responsible for converting electrical pulses generated by the motor neuron into electrical activity in muscle fibers, and is severely impaired in various diseases, such as Amyotrophic Lateral Sclerosis (ALS). Here, we proposed a novel technique to measure, for the first time, NMJ functionality in isotonic conditions, which better reflect muscle physiological activity.MethodsWe employed the in-situ testing technique, studied a proper placing of two pairs of wire electrodes for nerve and muscle stimulation, developed an extensive testing protocol, and proposed a novel parameter, the Isotonic Neurotransmission Failure (INF), to properly capture the impairments in neurotransmission during isotonic fatigue. We employed wild-type mice to assess the feasibility of the proposed technique, and the ALS model SOD1G93A mice to demonstrate the validity of the INF.ResultsResults confirmed the measurement accuracy in term of average value and coefficient of variation of the parameters measured through nerve stimulation in comparison with the corresponding values obtained for membrane stimulation. The INF values computed for the SOD1G93A tibialis anterior muscles pointed out an impairment of ALS mice during the isotonic fatigue test, whereas, as expected, their resistance to fatigue was higher.ConclusionsIn this work we devised a novel technique and a new parameter for a deep assessment of NMJ functionality in isotonic conditions, including fatigue, which is the most crucial condition for the neuronal signal transmission. This technique may be applied to other animal models, to unravel the mechanisms behind muscle-nerve impairments in other neurodegenerative pathologies.

Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders.

Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value.

Alterations in blood proteins in the prodromal stage of bipolar II disorders

Although early intervention may help prevent the progression of bipolar disorder, there are some controversies over early pharmacological intervention. In this study, we recruited 40 subjects in the prodromal stage of BD-II (BP), according to bipolar at-risk state criteria. We compared the expression of their plasma proteins with that of 48 BD-II and 75 healthy control (HC) to identify markers that could be detected in a high-risk state. The multiple reaction monitoring method was used to measure target peptide levels with high accuracy. A total of 26 significant peptides were identified through analysis of variance with multiple comparisons, of which 19 were differentially expressed in the BP group when compared to the BD-II and HC groups. Two proteins were overexpressed in the BP group; and were related to pro-inflammation and impaired neurotransmission. The other under-expressed peptides in the BP group were related to blood coagulation, immune reactions, lipid metabolism, and the synaptic plasticity. In this study, significant markers observed in the BP group have been reported in patients with psychiatric disorders. Overall, the results suggest that the pathophysiological changes included in BD-II had already occurred with BP, thus justifying early pharmacological treatment to prevent disease progression.

The involvement of oxidative stress, neuronal lesions, neurotransmission impairment, and neuroinflammation in acrylamide-induced neurotoxicity in C57/BL6 mice

The involvement of oxidative stress, neuronal lesions, neurotransmission impairment, and neuroinflammation in acrylamide-induced neurotoxicity in C57/BL6 mice

Toxicity of innovative antifouling additives on an early life stage of the oyster Crassostrea gigas: short- and long-term exposure effects.

Recent advances in nanotechnology have allowed the encapsulation of hazardous antifouling (AF) biocides in silica mesoporous nanocapsules (SiNC) reducing their short-term toxicity. However, the chronic effects of such novel nanoadditives remain understudied. The present study aimed to assess short- and long-term sub-lethal effects of soluble forms (DCOIT and Ag) and nanostructured forms (SiNC-DCOIT and SiNC-DCOIT-Ag) of two AF biocides and the "empty" nanocapsule (SiNC) on juveniles of Crassostrea gigas after 96h and 14days of exposure. Juvenile oysters exposed for a short period to free DCOIT and AgNO3 presented worse physiological status comparing with those exposed to the nanostructured forms. The long-term exposure to DCOIT and Ag+ caused an extensive biochemical impairment comparing with the tested nanomaterials, which included oxidative damage, activation of the antioxidant defense system, and neurotransmission impairment. Despite the negative effects mostly observed on the health condition index and AChE, the encapsulation of the abovementioned AF biocides into SiNC seems to be a technological advantage towards the development of AF nanoadditives with lower long-term toxicity comparing with the soluble forms of such biocides.

Distinct molecular pathways govern presynaptic homeostatic plasticity.

SummaryPresynaptic homeostatic plasticity (PHP) stabilizes synaptic transmission by counteracting impaired neurotransmitter receptor function through neurotransmitter release potentiation. PHP is thought to be triggered by impaired receptor function and to involve a stereotypic signaling pathway. However, here we demonstrate that different receptor perturbations that similarly reduce synaptic transmission result in different responses at the Drosophila neuromuscular junction. While receptor inhibition by the glutamate receptor (GluR) antagonist γ-D-glutamylglycine (γDGG) is not compensated by PHP, the GluR inhibitors Philanthotoxin-433 (PhTx) and Gyki-53655 (Gyki) induce compensatory PHP. Intriguingly, PHP triggered by PhTx and Gyki involve separable signaling pathways, including inhibition of distinct GluR subtypes, differential modulation of the active-zone scaffold Bruchpilot, and short-term plasticity. Moreover, while PHP upon Gyki treatment does not require genes promoting PhTx-induced PHP, it involves presynaptic protein kinase D. Thus, synapses not only respond differentially to similar activity impairments, but achieve homeostatic compensation via distinct mechanisms, highlighting the diversity of homeostatic signaling.