Exocytosis Research Articles

Ca2+ channel and active zone protein abundance intersects with input-specific synapse organization to shape functional synaptic diversity

Synaptic heterogeneity is a hallmark of nervous systems that enables complex and adaptable communication in neural circuits. To understand circuit function, it is thus critical to determine the factors that contribute to the functional diversity of synapses. We investigated the contributions of voltage-gated calcium channel (VGCC) abundance, spatial organization, and subunit composition to synapse diversity among and between synapses formed by two closely related Drosophila glutamatergic motor neurons with distinct neurotransmitter release probabilities (Pr). Surprisingly, VGCC levels are highly predictive of heterogeneous Pr among individual synapses of either low- or high-Pr inputs, but not between inputs. We find that the same number of VGCCs are more densely organized at high-Pr synapses, consistent with tighter VGCC-synaptic vesicle coupling. We generated endogenously tagged lines to investigate VGCC subunits in vivo and found that the α2δ–3 subunit Straightjacket along with the CAST/ELKS active zone (AZ) protein Bruchpilot, both key regulators of VGCCs, are less abundant at high-Pr inputs, yet positively correlate with Pr among synapses formed by either input. Consistently, both Straightjacket and Bruchpilot levels are dynamically increased across AZs of both inputs when neurotransmitter release is potentiated to maintain stable communication following glutamate receptor inhibition. Together, these findings suggest a model in which VGCC and AZ protein abundance intersects with input-specific spatial and molecular organization to shape the functional diversity of synapses.

Ca2+ channel and active zone protein abundance intersects with input-specific synapse organization to shape functional synaptic diversity.

Synaptic heterogeneity is a hallmark of nervous systems that enables complex and adaptable communication in neural circuits. To understand circuit function, it is thus critical to determine the factors that contribute to the functional diversity of synapses. We investigated the contributions of voltage-gated calcium channel (VGCC) abundance, spatial organization, and subunit composition to synapse diversity among and between synapses formed by two closely related Drosophila glutamatergic motor neurons with distinct neurotransmitter release probabilities (Pr). Surprisingly, VGCC levels are highly predictive of heterogeneous Pr among individual synapses of either low- or high-Pr inputs, but not between inputs. We find that the same number of VGCCs are more densely organized at high-Pr synapses, consistent with tighter VGCC-synaptic vesicle coupling. We generated endogenously tagged lines to investigate VGCC subunits in vivo and found that the α2δ-3 subunit Straightjacket along with the CAST/ELKS active zone (AZ) protein Bruchpilot, both key regulators of VGCCs, are less abundant at high-Pr inputs, yet positively correlate with Pr among synapses formed by either input. Consistently, both Straightjacket and Bruchpilot levels are dynamically increased across AZs of both inputs when neurotransmitter release is potentiated to maintain stable communication following glutamate receptor inhibition. Together, these findings suggest a model in which VGCC and AZ protein abundance intersects with input-specific spatial and molecular organization to shape the functional diversity of synapses.

Breaking the burst: Unveiling mechanisms behind fragmented network bursts in patient-derived neurons.

Fragmented network bursts (NBs) are observed as a phenotypic driver in many patient-derived neuronal networks on multi-electrode arrays (MEAs), but the pathophysiological mechanisms underlying this phenomenon are unknown. Here, we used our previously developed biophysically detailed in silico model to investigate these mechanisms. Fragmentation of NBs in our model simulations occurred only when the level of short-term synaptic depression (STD) was enhanced, suggesting that STD is a key player. Experimental validation with Dynasore, an STD enhancer, induced fragmented NBs in healthy neuronal networks invitro. Additionally, we showed that strong asynchronous neurotransmitter release, NMDA currents, or short-term facilitation (STF) can support the emergence of multiple fragments in NBs by producing excitation that persists after high-frequency firing stops. Our results provide important insights into disease mechanisms and potential pharmaceutical targets for neurological disorders modeled using human induced pluripotent stem cell (hiPSC)-derived neurons.

Group III metabotropic glutamate receptors: guardians against excitotoxicity in ischemic brain injury, with implications for neonatal contexts

AbstractThe group III metabotropic glutamate receptors (mGluRs), comprising mGluR4, mGluR6, mGluR7, and mGluR8, offer neuroprotective potential in mitigating excitotoxicity during ischemic brain injury, particularly in neonatal contexts. They are G-protein coupled receptors that inhibit adenylyl cyclase and reduce neurotransmitter release, mainly located presynaptically and acting as autoreceptors. This review aims to examine the differential expression and function of group III mGluRs across various brain regions such as the cortex, hippocampus, and cerebellum, with a special focus on the neonatal stage of development. Glutamate excitotoxicity plays a crucial role in the pathophysiology of brain ischemia in neonates. While ionotropic glutamate receptors are traditional targets for neuroprotection, their direct inhibition often leads to severe side effects due to their critical roles in normal neurotransmission and synaptic plasticity. Group III mGluRs provide a more nuanced and potentially safer approach by modulating rather than blocking glutamatergic transmission. Their downstream signaling cascade results in the regulation of intracellular calcium levels, neuronal hyperpolarization, and reduced neurotransmitter release, effectively decreasing excitotoxic signaling without completely suppressing essential glutamatergic functions. Importantly, the neuroprotective effects of group III mGluRs extend beyond direct modulation of glutamate release influencing glial cell function, neuroinflammation, and oxidative stress, all of which contribute to secondary injury cascades in brain ischemia. This comprehensive analysis of group III mGluRs multifaceted neuroprotective potential provides valuable insights for developing novel therapeutic strategies to combat excitotoxicity in neonatal ischemic brain injury.

Vesicle docking and fusion pore modulation by the neuronal calcium sensor Synaptotagmin-1.

Synaptotagmin-1 (Syt1) is a major calcium sensor for rapid neurotransmitter release in neurons and hormone release in many neuroendocrine cells. It possesses two tandem cytosolic C2 domains that bind calcium, negatively charged phospholipids, and the neuronal SNARE complex. Calcium binding to Syt1 triggers exocytosis, but how this occurs is not well understood. Syt1 has additional roles in docking dense core vesicles (DCV) and synaptic vesicles (SV) to the plasma membrane (PM) and in regulating fusion pore dynamics. Thus, Syt1 perturbations could affect release through vesicle docking, fusion triggering, fusion pore regulation, or a combination of these. Here, using a human neuroendocrine cell line, we show that neutralization of highly conserved polybasic patches in either C2 domain of Syt1 impairs both DCV docking and efficient release of serotonin from DCVs. Interestingly, the same mutations resulted in larger fusion pores and faster release of serotonin during individual fusion events. Thus, Syt1's roles in vesicle docking, fusion triggering, and fusion pore control may be functionally related.

Distinct input-specific mechanisms enable presynaptic homeostatic plasticity.

Synapses are endowed with the flexibility to change through experience, but must be sufficiently stable to last a lifetime. This tension is illustrated at the Drosophila neuromuscular junction (NMJ), where two motor inputs that differ in structural and functional properties co-innervate most muscles to coordinate locomotion. To stabilize NMJ activity, motor neurons augment neurotransmitter release following diminished postsynaptic glutamate receptor functionality, termed presynaptic homeostatic potentiation (PHP). How these distinct inputs contribute to PHP plasticity remains enigmatic. We have used a botulinum neurotoxin to selectively silence each input and resolve their roles in PHP, demonstrating that PHP is input-specific: Chronic (genetic) PHP selectively targets the tonic MN-Ib, where active zone remodeling enhances Ca2+ influx to promote increased glutamate release. In contrast, acute (pharmacological) PHP selectively increases vesicle pools to potentiate phasic MN-Is. Thus, distinct homeostatic modulations in active zone nanoarchitecture, vesicle pools, and Ca2+ influx collaborate to enable input-specific PHP expression.

Environmental Temperature Variation Affects Brain Lipid Composition in Adult Zebrafish (Danio rerio).

This study delves deeper into the impact of environmental temperature variations on the nervous system in teleost fish. Previous research has demonstrated that exposing adult zebrafish (Danio rerio) to 18 °C and 34 °C for 4 or 21 days induces behavioural changes compared to fish kept at a control temperature of 26 °C, suggesting alterations in the nervous system. Subsequent studies revealed that these temperature conditions also modify brain protein expression, indicating potential neurotoxic effects. The primary aim of this work was to investigate the effects of prolonged exposure (21 days) to 18 °C or 34 °C on the brain lipidomes of adult zebrafish compared to a control temperature. Analysis of the brain lipidome highlighted significant alteration in the relative abundances of specific lipid molecules at 18 °C and 34 °C, confirming distinct effects induced by both tested temperatures. Exposure to 18 °C resulted in an increase in levels of phospholipids, such as phosphatidylethanolamine, alongside a general reduction in levels of sphingolipids, including sphingomyelin. Conversely, exposure to 34 °C produced more pronounced effects, with increases in levels of phosphatidylethanolamine and those of various sphingolipids such as ceramide, gangliosides, and sphingomyelin, alongside a reduction in levels of ether phospholipids, including lysophosphatidylethanolamine ether, phosphatidylethanolamine ether, and phosphatidylglycerol ether, as well as levels of glycolipids like monogalactosyldiacylglycerol. These results, when integrated with existing proteomic and behavioural data, offer new insights into the effects of thermal variations on the nervous system in teleost fish. Specifically, our proteomic and lipidomic findings suggest that elevated temperatures may disrupt mitochondrial function, increase neuronal susceptibility to oxidative stress and cytotoxicity, alter axonal myelination, impair nerve impulse transmission, hinder synapse function and neurotransmitter release, and potentially lead to increased neuronal death. These findings are particularly relevant in the fields of cell biology, neurobiology, and ecotoxicology, especially in the context of global warming.

A Decrease in Autophagy Increases the Level of Collagen Type I Expression in Scleral Fibroblasts.

Autophagy dysregulation triggers extracellular matrix remodeling via changes in cellular collagen levels and protease secretion. However, the effect of autophagy on scleral extracellular matrix remodeling in the context of myopia is not fully understood. In this study, we measured the level of autophagy in sclera of form deprivation myopic guinea pigs; we also sought a correlation between the level of autophagy in human scleral fibroblasts and the extent of COL1A1 synthesis. We measured the level of COL1A1 expression and the levels of autophagic protein markers in scleral tissues in vivo using a form deprivation myopic guinea pig model. Rapamycin and chloroquine were respectively used to activate and inhibit autophagy in cultured human scleral fibroblasts. COL1A1 gene and protein expression levels were analyzed via quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence. Levels of autophagy-related proteins were assessed via Western blotting. The sclera of form deprivation myopic guinea pig eyes exhibited decreased expression of COL1A1 and increased expression level of autophagy. After chloroquine exposure, human scleral fibroblasts exhibited decreased autophagy and increased COL1A1 expression. Inhibition of scleral fibroblast autophagy increased COL1A1 expression at the gene and protein levels, thus explaining the effect of autophagy on collagen synthesis by scleral fibroblasts.

Paroxysmal dystonia results from the loss of RIM4 in Purkinje cells.

Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell type-specific role in cerebellar Purkinje cells that is essential for normal motor function. In the absence of RIM4, Purkinje cell intrinsic firing is reduced and caffeine-sensitive, and dendritic integration of climbing fibre input is disturbed. Mice lacking RIM4, but not mice lacking RIM1/2, selectively in Purkinje cells exhibit a severe, hours-long paroxysmal dystonia. These episodes can also be induced by caffeine, ethanol or stress and closely resemble the deficits seen with mutations of the PNKD (paroxysmal non-kinesigenic dystonia) gene. Our data reveal essential postsynaptic functions of RIM proteins and show non-overlapping specialized functions of a small isoform despite high homology to a single domain in the full-length proteins.

Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders.

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.

Synucleins As Biomarkers of Severity in Autism Spectrum Disorder.

Introduction Autism spectrum disorder (ASD) is a lifelong disorder affecting children quite early in life, manifested as delays in communication and stereotypic behaviors. To date, it is diagnosed clinically using the Diagnostic and Statistical Manual-5 (DSM-V) criteria due to the lack of biomarkers that can specifically denote the disorder. The role of synucleins in this context has been considered due to the increasing evidence of neurodegeneration in many autistic children. Synucleins are a group of soluble neuronal proteins primarily expressed in the central nervous system. They are of three types: α-, β-, and ɣ-synuclein. α-synuclein is involved in vesicle trafficking and release of neurotransmitters. There is no uniformity in the scientific community regarding their levels of autism, with few studies showing increasing levels and others to the contrary. Hence, the present study was conceived to analyze the levels of α-synuclein and β-synuclein in autistic children and to correlate with the disease severity. Objectives The main objectiveof the study was to assess the levels of α- and β-synuclein in autistic children of 2-8 years of age and to identify the correlation between the severity of core symptoms of autism and α- and β-synuclein levels. It is intended to assessthe possibility of using α- and β-synuclein/their ratioas a biomarker of the severity of autism. Materials and methods Plasma levels of α-synuclein and β-synuclein were measured in 160ASD childrenand 40 healthy age and sex-matched children by ELISA. Their symptom severity was assessed with CARS-2 ST and the Indian Scale of Autism Assessment (ISAA). Values of α- and β-synuclein were analyzed for correlation with the severity rating of ASD. Cut-off values ofα-synuclein and β-synuclein that discriminate the presence of autism and its severity were assessed using Jamovi 2.4.14 software. Results The results show that α-synuclein levels were significantly reduced (5.02 ± 0.586; range: 3.13-6.0 ng/ml) when compared with healthy controls (29.47 ± 18.62 ng/ml; range: 22.39- 36.56) with p < 0.001, and β-synuclein levels were elevated (1424 ng/ml ± 122; range: 1229-1616 ng/ml) when compared to control, though not significantly. Plasma levels of α-synuclein significantly correlate with disease severity with good diagnostic accuracy (86%), but β-synuclein levels did not correlate with severity. The fold changes of synucleins, especially the fold decrease in levels of α-synuclein, were discriminative for the diagnosis and severity with good sensitivity (93.6%), specificity (74.3%), positive predictive (92.6%), and negative predictive values (76.5%). The fold increase in β-synuclein did not have any significance in predicting the severity of autism. Conclusion The present study showed thatα-synuclein and β-synuclein were associated with ASD and can be used to assess its severity. A fold decrease inα-synuclein was found to have good discriminating value in differentiating the severity of autism. It may be of use especially in mild and high-functioning autism, when clinically distinguishing them may be difficult.

Targeted Temperature Management for Out-of-Hospital Cardiac Arrest Survivors.

Targeted temperature management (TTM), specifically therapeutic hypothermia, has been proposed to provide neuroprotective and mortality benefits for out-of-hospital cardiac arrest (OHCA) survivors. This proposition was based on small-scale trials from the early 2000s, leading to its incorporation into various international guidelines. The proposed neuroprotective mechanisms include reducing cerebral metabolic rate, stabilizing the blood-brain barrier, reducing the release of excitatory neurotransmitters, and suppressing apoptotic pathways. However, these early trials have been criticized for their high risk of bias and lack of standardized protocols. Recent evidence from more rigorously controlled randomized trials indicates no significant association between hypothermia and improved neurological outcomes or survival rates. This review explores the latest clinical evidence on TTM for OHCA patients, discussing the pathophysiology, evaluating the effectiveness of hypothermia through various clinical trials, and providing recommendations for future research and clinical practice.

A cause-effect relationship between uterine diseases and breast cancer: A bidirectional Mendelian randomization study

ObjectiveTo explore the cause-effect relationship between uterine diseases (UDs) and breast cancer (BC) and underlying mechanism of the cause-effect relationship, enhance understanding of the association between BC and UDs. MethodsA two-sample bidirectional Mendelian randomization (MR) analysis was conducted. We obtained summary statistics data from GWAS for BC, endometriosis, endometrial cancer (EC), uterine leiomyoma (UL), uterine polyps (UP), and cervical cancer (CC). Independent SNPs were selected as instrumental variables (IVs) for each disease. The inverse variance weighted (IVW) method was primary used for estimating the causal association between UDs and BC. To further evaluate the consistency and dependability of the results, we also utilized the weighted median, weighted mode, simple mode, and MR-Egger methods, along with sensitivity analyses. Furthermore, a supplementary analysis focusing on the variants linked to BC and UDs was conducted. This involved identifying corresponding genes and subsequently performing KEGG/GO analyses to investigate potential molecular mechanisms. ResultsThe results indicated significant associations between genetic susceptibility to endometriosis, EC, and UL with BC risk. The odds ratios (ORs) were as follows: endometriosis at 0.963 (95 % CI, 0.942–0.984; p = 7.11e-5), EC at 1.056 (95 % CI, 1.033–1.081; p = 2.39e-6), and UL at 1.027 (95 % CI, 1.006–1.048; p = 0.010). Conversely, the predisposition to BC inferred from genetic factors was markedly correlated with an elevated risk of EC indicated by an OR of 1.066 (95 % CI, 1.019–1.116; p = 0.006), and was correlated with UP risk (OR, 1.001,95 % CI, 1.000–1.002; p = 0.001).Sensitivity analyses provided weak evidence for these effects, suggesting that the study's outcomes are consistent and trustworthy. Further analysis of the genetic variants associated with BC, and these related genes are enriched in Cellular senescence, GnRH secretion, Phosphatidylinositol signaling system, and so on. ConclusionThis study corroborates the existence of a reciprocal causal relationship between BC and EC, as well as highlighting the substantial correlations between a genetic susceptibility to UL and endometriosis with BC. BC may exert their influence on EC and UP through Cellular senescence, GnRH secretion, and other pathways. These discoveries offer fresh perspectives on the genetic pathogenesis of BC and UDs, and can guide future experimental studies. Additionally, they lay down a groundwork for the development of tailored preventative and therapeutic strategies moving forward.

FOXM1 Upregulates O-GlcNAcylation Level Via The Hexosamine Biosynthesis Pathway to Promote Angiogenesis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) presents significant challenges in treatment and prognosis because of its aggressive nature and high metastatic potential. This study aims to investigate the role of the hexosamine biosynthesis pathway (HBP) and its association with HCC progression and prognosis. We identified SPP1 and FOXM1 as hub genes within the HBP pathway, showing their correlation with poor prognosis and late-stage progression. In addition, the analysis uncovered the complex participation of the HBP pathway in nutrients and oxygen reactions, PI3K-AKT signaling, AMPK activation, and angiogenesis regulation. The disruption of these pathways is pivotal in influencing the growth and progression of HCC. Targeting the HBP presents a promising therapeutic approach to modulate the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. In addition, FOXM1 was identified as the HBP pathway regulator, influencing cellular O-GlcNAcylation level and VEGF secretion, thereby promoting angiogenesis in HCC. Inhibition of O-GlcNAcylation significantly hindered angiogenesis, which is suggested as a potential avenue for therapeutic intervention. Our research demonstrates the practicality of using the HBP-related gene as a prognostic marker in liver cancer patients and suggests targeting FOXM1 as a novel avenue for personalized therapy.

From Frog Muscle to Brain Neurons: Joys and Sorrows in Neuroscience.

One element, potassium, can be identified as the connecting link in the research of Czech neurophysiologist Prof. František Vyskočil. It accompanied him from the first student experiments on the frog muscle (Solandt effect) via sodium-potassium pump and quantum and non-quantum release of neurotransmitters (e.g. acetylcholine) to the most appreciated work on the reversible leakage of K+ from brain neurons during the Leao´s spreading cortical depression, often preceding migraine. He used a wide range of methods at the systemic, cellular and genetic levels. The electrophysiology and biochemistry of nerve-muscle contacts and synapses in the muscles and brain led to a range of interesting findings and discoveries on normal, denervated and hibernating laboratory mammals and in tissue cultures. Among others, he co-discovered the facilitating effects of catecholamines (adrenaline in particular) by end-plate synchronization of individual evoked quanta. This helps to understand the general effectiveness of nerve-muscle performance during actual stress. After the transition of the Czech Republic to capitalism, together with Dr. Josef Zicha from our Institute, he was an avid promoter of scientometry as an objective system of estimating a scientist´s success in basic research (journal Vesmír, 69: 644-645, 1990 in Czech).

Motor point stimulation activates fewer Ia-sensory nerves than peripheral nerve stimulation in human soleus muscle.

Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) are noninvasive techniques used to induce muscle contraction, aiding motor function restoration in individuals with neurological disorders. Understanding sensory inputs from PNS and MPS is crucial for facilitating neuroplasticity and restoring impaired motor function. Although previous studies suggest that MPS could induce Ia-sensory inputs less than PNS, experimental evidence supporting this claim is insufficient. Here, we implemented a conditioning paradigm combining transcutaneous spinal cord stimulation (tSCS) with PNS or MPS to investigate their Ia-sensory inputs. This paradigm induces postactivation depression of spinal reflexes associated with transient decreases in neurotransmitter release from Ia-afferent terminals, allowing us to examine the Ia-sensory input amount from PNS and MPS based on the depression degree. We hypothesized that MPS would induce less postactivation depression than PNS. Thirteen individuals underwent MPS and PNS on the soleus muscle as conditioning stimuli, with tSCS applied to the skin between the spinous processes (L1-L2) as test stimuli. PNS- and MPS-conditioned spinal reflexes were recorded at five interstimulus intervals (ISIs) and four intensities. Results revealed that all PNS conditioning showed significant decreases in spinal reflex amplitudes, indicating postactivation depression. Furthermore, PNS conditioning exhibited greater depression for shorter ISIs and higher conditioning intensities. In contrast, MPS conditioning demonstrated intensity-dependent depression, but without all-conditioning depression and clear ISI dependency as seen in PNS conditioning. In addition, PNS induced significantly greater depression than MPS across most conditions. Our findings provide experimental evidence supporting the conclusion that MPS activates Ia-sensory nerves less than PNS.NEW & NOTEWORTHY Peripheral nerve stimulation (PNS) and motor point stimulation (MPS) induce neuroplasticity, but differences in their effects on Ia-sensory inputs are unclear. We investigated their Ia-sensory inputs using a conditioning paradigm with spinal reflexes. Results showed that PNS conditioning significantly inhibited spinal reflexes than MPS conditioning, indicating greater postactivation depression due to Ia-sensory nerve activation. These findings provide experimental evidence that MPS activates Ia-sensory nerves to a lesser extent than PNS, enhancing our understanding of neuroplasticity.

Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review.

The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.

Magnesium (Mg2+): Essential Mineral for Neuronal Health: From Cellular Biochemistry to Cognitive Health and Behavior Regulation.

Magnesium (Mg2+) is a crucial mineral involved in numerous cellular processes critical for neuronal health and function. This review explores the multifaceted roles of Mg2+, from its biochemical interactions at the cellular level to its impact on cognitive health and behavioral regulation. Mg2+ acts as a cofactor for over 300 enzymatic reactions, including those involved in ATP synthesis, nucleic acid stability, and neurotransmitter release. It regulates ion channels, modulates synaptic plasticity, and maintains the structural integrity of cell membranes, which are essential for proper neuronal signaling and synaptic transmission. Recent studies have highlighted the significance of Mg2+ in neuroprotection, showing its ability to attenuate oxidative stress, reduce inflammation, and mitigate excitotoxicity, thereby safeguarding neuronal health. Furthermore, Mg2+ deficiency has been linked to a range of neuropsychiatric disorders, including depression, anxiety, and cognitive decline. Supplementation with Mg2+, particularly in the form of bioavailable compounds such as Magnesium-L-Threonate (MgLT), Magnesium-Acetyl-Taurate (MgAT), and other Magnesium salts, has shown some promising results in enhancing synaptic density, improving memory function, and alleviating symptoms of mental health disorders. This review highlights significant current findings on the cellular mechanisms by which Mg2+ exerts its neuroprotective effects and evaluates clinical and preclinical evidence supporting its therapeutic potential. By elucidating the comprehensive role of Mg2+ in neuronal health, this review aims to underscore the importance of maintaining optimal Mg2+ levels for cognitive function and behavioral regulation, advocating for further research into Mg2+ supplementation as a viable intervention for neuropsychiatric and neurodegenerative conditions.

The Role of α-Synuclein in Etiology of Neurodegenerative Diseases.

A presynaptic protein called α-synuclein plays a crucial role in synaptic function and neurotransmitter release. However, its misfolding and aggregation have been implicated in a variety of neurodegenerative diseases, particularly Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Emerging evidence suggests that α-synuclein interacts with various cellular pathways, including mitochondrial dysfunction, oxidative stress, and neuroinflammation, which contributes to neuronal cell death. Moreover, α-synuclein has been involved in the propagation of neurodegenerative processes through prion-like mechanisms, where misfolded proteins induce similar conformational changes in neighboring neurons. Understanding the multifaced roles of α-synuclein in neurodegeneration not only aids in acquiring more knowledge about the pathophysiology of these diseases but also highlights potential biomarkers and therapeutic targets for intervention in alpha-synucleinopathies. In this review, we provide a summary of the mechanisms by which α-synuclein contributes to neurodegenerative processes, focusing on its misfolding, oligomerization, and the formation of insoluble fibrils that form characteristic Lewy bodies. Furthermore, we compare the potential value of α-synuclein species in diagnosing and differentiating selected neurodegenerative diseases.

Tackling Neuroinflammation in Cognitive Disorders with Single-Targeted and Multi-Targeted Histamine H3 Receptor Modulators.

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here.