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Fulltext Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord

Davis OC, Dickie AC, Mustapa MB, Boyle KA, Browne TJ, Gradwell MA, et al.

Sci Rep, 2023 Jul 18;13(1):11561.
PMID: 37464016 DOI: 10.1038/s41598-023-38605-9

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.

Matched MeSH terms: Synapses
Functional Neuroproteomics: An Imperative Approach for Unravelling Protein Implicated Complexities of Brain

Husain I, Ahmad W, Ali A, Anwar L, Nuruddin SM, Ashraf K, et al.

CNS Neurol Disord Drug Targets, 2021;20(7):613-624.
PMID: 33530918 DOI: 10.2174/1871527320666210202121624

A proteome is defined as a comprehensive protein set either of an organ or an organism at a given time and under specific physiological conditions. Accordingly, the study of the nervous system's proteomes is called neuroproteomics. In the neuroproteomics process, various pieces of the nervous system are "fragmented" to understand the dynamics of each given sub-proteome in a much better way. Functional proteomics addresses the organisation of proteins into complexes and the formation of organelles from these multiprotein complexes that control various physiological processes. Current functional studies of neuroproteomics mainly talk about the synapse structure and its organisation, the major building site of the neuronal communication channel. The proteomes of synaptic vesicle, presynaptic terminal, and postsynaptic density, have been examined by various proteomics techniques. The objectives of functional neuroproteomics are: to solve the proteome of single neurons or astrocytes grown in cell cultures or from the primary brain cells isolated from tissues under various conditions, to identify the set of proteins that characterize specific pathogenesis, or to determine the group of proteins making up postsynaptic or presynaptic densities. It is usual to solve a particular sub-proteome like the heat-shock response proteome or the proteome responding to inflammation. Post-translational protein modifications alter their functions and interactions. The techniques to detect synapse phosphoproteome are available. However, techniques for the analysis of ubiquitination and sumoylation are under development.

Matched MeSH terms: Synapses/physiology
Fulltext Prediction of clinical symptoms of Schizophrenia based on COMT Methylation marker

Nour El Huda Abd Rahim, Mohd Nabil Fikri Rahim, Norsidah Ku Zaifah, Hanisah Mohd Noor, Kartini Abdullah, Norlelawati A. Talib

International Medical Journal Malaysia, 2017;16(11):19-19.
MyJurnal

The dopamine hypothesis of schizophrenia is based on the fact that hyperdopaminergic
state is involved in causing psychosis and antipsychotic drugs block the
dopamine receptor. COMT regulates the homeostatic levels of neurotransmitter
dopamine in the synapses and plays a role in the neurocognitive function. The
dysregulation of dopamine in the prefrontal cortex influences the cognitive function and
the severity of the psychotic symptoms in schizophrenia. During epigenetic event,
methylated COMT gene may cause reduction in its expression and contribute to the
clinical presentation of schizophrenia. Therefore, the aim of this study was to assess the
feasibility of using COMT DNA methylation for the prediction of specific psychotic
presentation of schizophrenia. (Copied from article).

Matched MeSH terms: Synapses
Associable representations as field of influence for dynamic cognitive processes

Cacha LA, Poznanski RR

J Integr Neurosci, 2011 Dec;10(4):423-37.
PMID: 22262534

In earlier models, synaptic plasticity forms the basis for cellular signaling underlying learning and memory. However, synaptic computation of learning and memory in the brain remains controversial. In this paper, we discuss ways in which synaptic plasticity remodels subcellular networks by deflecting trajectories in neuronal state-space as regulating patterns for the synthesis of dynamic continuity that form cognitive networks of associable representations through endogenous dendritic coding to consolidate memory.

Matched MeSH terms: Synapses/physiology
Plasma exosomes carrying mmu-miR-146a-5p and Notch signalling pathway-mediated synaptic activity in schizophrenia

Wang Z, Wu T, Hu H, Alabed AAA, Cui G, Sun L, et al.

J Psychiatry Neurosci, 2024;49(4):E265-E281.
PMID: 39209459 DOI: 10.1503/jpn.230118

BACKGROUND: Schizophrenia is characterized by a complex interplay of genetic and environmental factors, leading to alterations in various molecular pathways that may contribute to its pathogenesis. Recent studies have shown that exosomal microRNAs could play essential roles in various brain disorders; thus, we sought to explore the potential molecular mechanisms through which microRNAs in plasma exosomes are involved in schizophrenia.
METHODS: We obtained sequencing data sets (SUB12404730, SUB12422862, and SUB12421357) and transcriptome sequencing data sets (GSE111708, GSE108925, and GSE18981) from mouse models of schizophrenia using the Sequence Read Archive and the Gene Expression Omnibus databases, respectively. We performed differential expression analysis on mRNA to identify differentially expressed genes. We conducted Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to determine differentially expressed genes. Subsequently, we determined the intersection of differentially expressed microRNAs in plasma exosomes and in prefrontal cortex tissue. We retrieved downstream target genes of mmu-miR-146a-5p from TargetScan and used Cytoscape to visualize and map the microRNA-target gene regulatory network. We conducted in vivo experiments using MK-801-induced mouse schizophrenia models and in vitro experiments using cultured mouse neurons. The role of plasma exosomal miR-146a-5p in schizophrenia was validated using a cell counting kit, detection of lactate dehydrogenase, dual-luciferase assay, quantitative reverse transcription polymerase chain reaction, and Western blot analysis.
RESULTS: Differential genes were mainly enriched in synaptic regulation-related functions and pathways and were associated with neuronal degeneration. We found that mmu-miR-146a-5p was highly expressed in both prefrontal cortical tissue and plasma exosomes, which may be transferred to lobe cortical vertebral neurons, leading to the synergistic dysregulation of gene network functions and, therefore, promoting schizophrenia development. We found that mmu-miR-146a-5p may inhibit the Notch signalling pathway-mediated synaptic activity of mouse pyramidal neurons in the lobe cortex by targeting NOTCH1, which in turn could promote the onset and development of schizophrenia in mice.
LIMITATIONS: The study's findings are based on animal models and in vitro experiments, which may not fully replicate the complexity of human schizophrenia.
CONCLUSION: Our findings suggest that mmu-miR-146a-5p in plasma-derived exosomes may play an important role in the pathogenesis of schizophrenia. Our results provide new insights into the underlying molecular mechanisms of the disease.

Matched MeSH terms: Synapses/metabolism
Fulltext Early childhood development and play: a review

Selim Ahmed

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):11-11.
MyJurnal

Introduction: Early childhood development (ECD) refers to cognitive, emotional and social development of young children. First three years of life are very crucial for ECD because during this time, brain grows fastest and is most responsive and receptive. Plenty of new connections (synapses) are formed in brain so that children acquire 85% of adult’s brain volume by this age. Proper nutrition and positive stimulation are essential during this time. Play positively stimulates the brain and helps to create more, healthy inter-neuronal connections. The objective of this review was to make a constellation of research works and explore to learn the concept of ECD and its relationship with play. Methods: An extensive literature search was done using the key words: ‘early childhood development and play’; ‘play and brain development in children’; ‘neuroplasticity and play’; ‘how do children learn’; ‘synaptic connections and early childhood development’; and ‘can play make children intelligent’. The databases explored for the resources included Medline (PubMed), PsycINFO, Teacher Reference Center, Child Encyclopedia, Health & Education Advice & Resource Team (HEART) database, Catholic Relief Services database, UNICEF & World Bank databases, and Cochrane review. Results: The result of the review work showed that play has a temporal and linear relationship with cognitive and social development among preschool children. Conclusion: In this era of screen addiction, parents spend free time in social media and the kids playing or watching video games. It is contextual to propagate the concept of ECD and raise the awareness so that parents are motivated to spend more time playing with their children. No investment in human capital can be worth more than this.

Matched MeSH terms: Synapses
Fulltext Cholinesterase inhibitors from botanicals

Ahmed F, Ghalib RM, Sasikala P, Ahmed KK

Pharmacogn Rev, 2013 Jul;7(14):121-30.
PMID: 24347920 DOI: 10.4103/0973-7847.120511

Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed.

Matched MeSH terms: Synapses
The role of neuron-glia interactions in the emergence of ultra-slow oscillations

Chan SC, Mok SY, Ng DW, Goh SY

Biol Cybern, 2017 Dec;111(5-6):459-472.
PMID: 29128889 DOI: 10.1007/s00422-017-0740-z

Ultra-slow cortical oscillatory activity of 1-100 mHz has been recorded in human by electroencephalography and in dissociated cultures of cortical rat neurons, but the underlying mechanisms remain to be elucidated. This study presents a computational model of ultra-slow oscillatory activity based on the interaction between neurons and astrocytes. We predict that the frequency of these oscillations closely depends on activation of astrocytes in the network, which is reflected by oscillations of their intracellular calcium concentrations with periods between tens of seconds and minutes. An increase of intracellular calcium in astrocytes triggers the release of adenosine triphosphate from these cells which may alter transmission at nearby synapses by increasing or decreasing neurotransmitter release. These results provide theoretical support for the emerging awareness of astrocytes as active players in the regulation of neural activity and identify neuron-astrocyte interactions as a potential primary mechanism for the emergence of ultra-slow cortical oscillations.

Matched MeSH terms: Synapses/physiology*
Fulltext Zinc transporter-3 [SLC30A3(rs11126936)]polymorphismis associated with major depressive disorderin Asian subjects

Lye, Munn-Sann, Aishah-Farhana Shahbudin, Tey, Yin-Yee, Tor, Yin-Sim, Ling, King-Hwa, Normala Ibrahim, et al.

Neuroscience Research Notes, 2019;2(3):20-28.
MyJurnal

Major depressive disorder (MDD) compromises the individual’s capacity for self-care and productivity. Single nucleotide polymorphisms (SNP) of a number of genes have been associated with MDD. The zinc transporter-3 protein, encoded by the ZnT3 (SLC30A3) gene, maintains zinc-glutamate homeostasis at the glutamatergic synapse, a disruption of which increases risk of MDD. We hypothesise that variation in SLC30A3 (rs11126936)SNP increases risk of MDD. We recruited 300 MDD cases and 300 controls, matched in theratio of 1:1 by age, gender and ethnicity. PCR-restriction fragment length polymorphism analysis was used in DNA genotyping, validated by sequencing 10%of samples. Deviation from the Hardy-Weinberg equilibrium was tested using the chi-square test. Conditional logistic regression was used to estimate adjusted odds ratios, controlling for age, gender, ethnicity, occupation and family monthly income.Genotypes G/G and G/T showed two times greater odds of developing MDD compared to variant genotype T/T (OR=1.983, 95% CI=1.031-3.815; p=0.040 and OR=2.232, 95% CI=1.100-4.533; p=0.026 respectively). Carriers of genotypes G/G and G/T of the SNP rs11126936 in SLC30A3are associated with increased risk of MDD.

Matched MeSH terms: Synapses
Glutamate receptors and transporters as comparative cues to the glutamatergic circuits of the avian and mammalian brain

Islam, M.R., Muzaimi, M., Abdullah, J.M.

Orient Neuron Nexus, 2011;2(1):2-9.
MyJurnal

Glutamate is the principal excitatory neurotransmitter in the central nervous system, and plays important roles in both physiological and pathological neuronal processes. Current understanding of the exact mechanisms involved in glutamate-induced neuronal excitotoxicity, in which excessive glutamate causes neuronal dysfunction and degeneration, whether acute or chronic, remain elusive. Conditions, due to acute insults such as ischaemia and traumatic brain injury, and chronic neurodegenerative disorders such as multiple sclerosis and motor neuron disease, suffer from the lack of translational neuroprotection in clinical setting to tackle glutamate excitotoxicity despite steady growth of animal studies that revealed complex cell death pathway interactions. In addition, glutamates are also released by non-neuronal cells including astrocytes and oligodendroglia. Thus, attempts to elucidate this complexity are closely related to our understanding of the glutamatergic circuitry in the brain. Neuronal cells develop a glutamatergic system at glutamatergic synapses that utilise glutamate as an intercellular signaling molecule to characterise the output, input, and termination of this signaling. As to signal input, various kinds of glutamate receptors have been identified and characterized. Na+-dependent glutamate transporters at the plasma membrane are responsible for the signal termination through sequestration of glutamate from the synaptic cleft. The signal output systems comprise vesicular storage and subsequent exocytosis of glutamate by using vesicular glutamate transporters. Similar to the mammalian brain, the regional differences of glutamatergic neurons and glutamate receptor neurons suggest many glutamatergic projections in the avian brain, as supported by recent evidence of glutamate-related genes distribution. Glutamatergic target areas are expected to show high activity of glutamate transporters that remove released glutamate from the synaptic clefts. This review summarises and compares glutamatergic circuits in the avian and mammalian brain, particularly in the olfactory pathway, the paffial organization of glutamatergic neurons and connection with the striatum, hippocampal-septal pathway, visual and auditory pathways, and granule cell-Purkinje cell pathway in the cerebellum. Comparative appreciation of these glutamatergic circuits, particularly with the localisation and/or expression of specific subtypes of glutamate transporters, would provide the morphological basis for physiological and pharmacological designs that supplement existing animal studies of the current proposed mechanisms that underlie glutamate-induced neuronal excitotoxicity.

Matched MeSH terms: Synapses
Fulltext Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations

Jha NK, Ojha S, Jha SK, Dureja H, Singh SK, Shukla SD, et al.

J Mol Neurosci, 2021 Nov;71(11):2192-2209.
PMID: 33464535 DOI: 10.1007/s12031-020-01767-6

The coronavirus disease 2019 (COVID-19) pandemic is an issue of global significance that has taken the lives of many across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for its pathogenesis. The pulmonary manifestations of COVID-19 have been well described in the literature. Initially, it was thought to be limited to the respiratory system; however, we now recognize that COVID-19 also affects several other organs, including the nervous system. Two similar human coronaviruses (CoV) that cause severe acute respiratory syndrome (SARS-CoV-1) and Middle East respiratory syndrome (MERS-CoV) are also known to cause disease in the nervous system. The neurological manifestations of SARS-CoV-2 infection are growing rapidly, as evidenced by several reports. There are several mechanisms responsible for such manifestations in the nervous system. For instance, post-infectious immune-mediated processes, direct virus infection of the central nervous system (CNS), and virus-induced hyperinflammatory and hypercoagulable states are commonly involved. Guillain-Barré syndrome (GBS) and its variants, dysfunction of taste and smell, and muscle injury are numerous examples of COVID-19 PNS (peripheral nervous system) disease. Likewise, hemorrhagic and ischemic stroke, encephalitis, meningitis, encephalopathy acute disseminated encephalomyelitis, endothelialitis, and venous sinus thrombosis are some instances of COVID-19 CNS disease. Due to multifactorial and complicated pathogenic mechanisms, COVID-19 poses a large-scale threat to the whole nervous system. A complete understanding of SARS-CoV-2 neurological impairments is still lacking, but our knowledge base is rapidly expanding. Therefore, we anticipate that this comprehensive review will provide valuable insights and facilitate the work of neuroscientists in unfolding different neurological dimensions of COVID-19 and other CoV associated abnormalities.

Matched MeSH terms: Synapses/virology

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