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Medicine Apr 2024Cerebral palsy (CP) is the most common disabling disease in children, and motor dysfunction is the core symptom of CP. Although relevant risk factors have been found to... (Observational Study)
Observational Study
Cerebral palsy (CP) is the most common disabling disease in children, and motor dysfunction is the core symptom of CP. Although relevant risk factors have been found to be closely associated with CP: congenital malformations, multiple gestation, prematurity, intrauterine inflammation and infection, birth asphyxia, thrombophilia, and perinatal stroke. Its important pathophysiological mechanism is amniotic fluid infection and intraamniotic inflammation leading to fetal developing brain damage, which may last for many years. However, the molecular mechanism of CP is still not well explained. This study aimed to use bioinformatics to identify key biomarker-related signaling pathways in CP. The expression profile of children with CP was selected from the Gene Expression Comprehensive Database, and the CP disease gene data set was obtained from GeneCards. A protein-protein interaction network was established and functional enrichment analysis was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. A total of 144 differential key intersection genes and 10 hub genes were identified through molecular biology. Gene Ontology functional enrichment analysis results show that differentially expressed genes are mainly concentrated in biological processes, such as immune response and neurogenesis. The cellular components involved mainly include axons, postsynaptic membranes, etc, and their molecular functions mainly involve proteoglycan binding, collagen binding, etc. Kyoto Encyclopedia of Genes and Genomes analysis shows that the intersection genes are mainly in signaling pathways related to the immune system, inflammatory response, and nervous system, such as Th17 cell differentiation, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, NF-κB signaling pathway, axon guidance, PI3K-Akt signaling pathway, HIF-1 signaling pathway, gap junction, etc. Jak-STAT signaling pathway, mTOR signaling pathway, and related hub genes regulate immune cells and inflammatory factors and play an important role in the development and progression of CP.
Topics: Child; Female; Pregnancy; Humans; Cerebral Palsy; Phosphatidylinositol 3-Kinases; Biomarkers; Brain Injuries; Computational Biology; Inflammation
PubMed: 38640267
DOI: 10.1097/MD.0000000000037828 -
BioRxiv : the Preprint Server For... Apr 2024Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher...
Precise connectivity between specific neurons is essential for the formation of the complex neural circuitry necessary for executing intricate motor behaviors and higher cognitive functions. While -interactions between synaptic membrane proteins have emerged as crucial elements in orchestrating the assembly of these neural circuits, the synaptic surface proteins involved in neuronal wiring remain largely unknown. Here, using unbiased single-cell transcriptomic and mouse genetic approaches, we uncover that the neurexin family of genes enables olfactory sensory neuron (OSNs) axons to form appropriate synaptic connections with their mitral and tufted (M/T) cell synaptic partners, within the mammalian olfactory system. Neurexin isoforms are differentially expressed within distinct populations of OSNs, resulting in unique pattern of neurexin expression that is specific to each OSN type, and synergistically cooperate to regulate axonal innervation, guiding OSN axons to their designated glomeruli. This process is facilitated through the interactions of neurexins with their postsynaptic partners, including neuroligins, which have distinct expression patterns in M/T cells. Our findings suggest a novel mechanism underpinning the precise assembly of olfactory neural circuits, driven by the -interaction between neurexins and their ligands.
PubMed: 38617205
DOI: 10.1101/2024.04.01.587570 -
International Journal of Molecular... Mar 2024Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics.... (Review)
Review
Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (/ lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.
Topics: Humans; Animals; Mice; Mice, Inbred MRL lpr; Chronic Pain; Interleukin-18; AMP-Activated Protein Kinases; Glutamic Acid; Interleukin-1beta; Lupus Erythematosus, Systemic; Analgesics
PubMed: 38612414
DOI: 10.3390/ijms25073602 -
The Journal of Biological Chemistry May 2024Synapse formation depends on the coordinated expression and regulation of scaffold proteins. The JNK family kinases play a role in scaffold protein regulation, but the...
Synapse formation depends on the coordinated expression and regulation of scaffold proteins. The JNK family kinases play a role in scaffold protein regulation, but the nature of this functional interaction in dendritic spines requires further investigation. Here, using a combination of biochemical methods and live-cell imaging strategies, we show that the dynamics of the synaptic scaffold molecule SAP102 are negatively regulated by JNK inhibition, that SAP102 is a direct phosphorylation target of JNK3, and that SAP102 regulation by JNK is restricted to neurons that harbor mature synapses. We further demonstrate that SAP102 and JNK3 cooperate in the regulated trafficking of kainate receptors to the cell membrane. Specifically, we observe that SAP102, JNK3, and the kainate receptor subunit GluK2 exhibit overlapping expression at synaptic sites and that modulating JNK activity influences the surface expression of the kainate receptor subunit GluK2 in a neuronal context. We also show that SAP102 participates in this process in a JNK-dependent fashion. In summary, our data support a model in which JNK-mediated regulation of SAP102 influences the dynamic trafficking of kainate receptors to postsynaptic sites, and thus shed light on common pathophysiological mechanisms underlying the cognitive developmental defects associated with diverse mutations.
Topics: Animals; Humans; Rats; Cell Membrane; Dendritic Spines; GluK2 Kainate Receptor; Hippocampus; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mitogen-Activated Protein Kinase 10; Neurons; Neuropeptides; Phosphorylation; Protein Transport; Receptors, Kainic Acid; Synapses; Cells, Cultured
PubMed: 38582451
DOI: 10.1016/j.jbc.2024.107263 -
Frontiers in Synaptic Neuroscience 2024Epileptiform activity is the most striking result of hyperexcitation of a group of neurons that can occur in different brain regions and then spread to other sites....
INTRODUCTION
Epileptiform activity is the most striking result of hyperexcitation of a group of neurons that can occur in different brain regions and then spread to other sites. Later it was shown that these rhythms have a cellular correlate called paroxysmal depolarization shift (PDS). In 13-15 DIV neuron-glial cell culture, inhibition of the GABA(A) receptors induces bursts of action potential in the form of clasters PDS and oscillations of intracellular Ca concentration ([Ca]). We demonstrate that GABAergic neurons expressing calcium-permeable AMPA receptors (CP-AMPARs) as well as Kv7-type potassium channels regulate hippocampal glutamatergic neurons' excitability during epileptiform activity in culture.
METHODS
A combination of whole-cell patch-clamp in current clamp mode and calcium imaging microscopy was used to simultaneously register membrane potential and [Ca] level. To identify GABAergic cell cultures were fixed and stained with antibodies against glutamate decarboxylase GAD 65/67 and neuron-specific enolase (NSE) after vital [Ca] imaging.
RESULTS AND DISCUSSION
It was shown that CP-AMPARs are involved in the regulation of the PDS clusters and [Ca] pulses accompanied them. Activation of CP-AMPARs of GABAergic neurons is thought to cause the release of GABA, which activates the GABA(B) receptors of other GABAergic interneurons. It is assumed that activation of these GABA(B) receptors leads to the release of beta-gamma subunits of Gi protein, which activate potassium channels, resulting in hyperpolarization and inhibition of these interneurons. The latter causes disinhibition of glutamatergic neurons, the targets of these interneurons. In turn, the CP-AMPAR antagonist, NASPM, has the opposite effect. Measurement of membrane potential in GABAergic neurons by the patch-clamp method in whole-cell configuration demonstrated that NASPM suppresses hyperpolarization in clusters and individual PDSs. It is believed that Kv7-type potassium channels are involved in the control of hyperpolarization during epileptiform activity. The blocker of Kv7 channels, XE 991, mimicked the effect of the CP-AMPARs antagonist on PDS clusters. Both drugs increased the duration of the PDS cluster. In turn, the Kv7 activator, retigabine, decreased the duration of the PDS cluster and Ca pulse. In addition, retigabine led to deep posthyperpolarization at the end of the PDS cluster. The Kv7 channel is believed to be involved in the formation of PDS, as the channel blocker reduced the rate of hyperpolarization in the PDS almost three times. Thus, GABAergic neurons expressing CP-AMPARs, regulate the membrane potential of innervated glutamatergic neurons by modulating the activity of postsynaptic potassium channels of other GABAergic neurons.
PubMed: 38577639
DOI: 10.3389/fnsyn.2024.1349984 -
Proceedings of the National Academy of... Apr 2024Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters...
Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABA receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABA receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.
Topics: Synapses; Receptors, Cholinergic; Synaptic Transmission; Motor Neurons; Receptors, GABA-A; gamma-Aminobutyric Acid; Neurotransmitter Agents; Cholinergic Agents; Receptors, Presynaptic
PubMed: 38568976
DOI: 10.1073/pnas.2318041121 -
Cellular and Molecular Neurobiology Apr 2024The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the...
The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-K) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca concentrations against I/R injury.
Topics: Animals; Mice; Mice, Inbred C57BL; Ischemic Postconditioning; Receptors, N-Methyl-D-Aspartate; Brain Injuries; Adenosine Triphosphate; Calcium Channels; Ruthenium Compounds
PubMed: 38568450
DOI: 10.1007/s10571-024-01464-7 -
BioRxiv : the Preprint Server For... Mar 2024WWC2 (WW and C2 domain-containing protein) is implicated in several neurological disorders, however its function in the brain has yet to be determined. Here, we...
WWC2 (WW and C2 domain-containing protein) is implicated in several neurological disorders, however its function in the brain has yet to be determined. Here, we demonstrate that WWC2 interacts with inhibitory but not excitatory postsynaptic scaffolds, consistent with prior proteomic identification of WWC2 as a putative component of the inhibitory postsynaptic density. Using mice lacking WWC2 expression in excitatory forebrain neurons, we show that WWC2 suppresses GABA R incorporation into the plasma membrane and regulates HAP1 and GRIP1, which form a complex promoting GABA R recycling to the membrane. Inhibitory synaptic transmission is dysregulated in CA1 pyramidal cells lacking WWC2. Furthermore, unlike the WWC2 homolog KIBRA (WWC1), a key regulator of AMPA receptor trafficking at excitatory synapses, deletion of WWC2 does not affect synaptic AMPAR expression. In contrast, loss of KIBRA does not affect GABA R membrane expression. These data reveal unique, synapse class-selective functions for WWC proteins as regulators of ionotropic neurotransmitter receptors and provide insight into mechanisms regulating GABA R membrane expression.
PubMed: 38559047
DOI: 10.1101/2024.03.11.584487 -
Journal of Personalized Medicine Feb 2024The thymus is a lymphoid organ involved in the differentiation of T cells, and has a central role in the physiopathogenesis of Myasthenia Gravis (MG). This connection is... (Review)
Review
The thymus is a lymphoid organ involved in the differentiation of T cells, and has a central role in the physiopathogenesis of Myasthenia Gravis (MG). This connection is proved by a series of changes in the level of neuromuscular junctions, which leads to a decrease in the amplitude of the action potential in the post-synaptic membrane. Because of this, the presence of anti-cholinergic receptor antibodies (AChR), characteristic of MG, is found, which causes the progressive regression of the effect of acetylcholine at the level of neuromuscular junctions, with the appearance of muscle weakness. The thymectomy is a surgical variant of drug therapy administered to patients with MG. In the case of patients with nonthymomatous MG, thymectomy has become a therapeutic standard, despite the fact that there is no solid scientific evidence to explain its positive effect. Videothoracoscopic surgery or robotic surgery led to a decrease in the length of hospital stay for these patients. This paper aims to synthesize the information presented in the literature in order to create a background for the perspectives of thymectomy.
PubMed: 38540983
DOI: 10.3390/jpm14030241 -
PloS One 2024Chromodomain helicase DNA binding domain (CHD) proteins, including CHD7 and CHD8, remodel chromatin to enable transcriptional programs. Both proteins are important for...
Chromodomain helicase DNA binding domain (CHD) proteins, including CHD7 and CHD8, remodel chromatin to enable transcriptional programs. Both proteins are important for proper neural development as heterozygous mutations in Chd7 and Chd8 are causative for CHARGE syndrome and correlated with autism spectrum disorders, respectively. Their roles in mature neurons are poorly understood despite influencing the expression of genes required for cell adhesion, neurotransmission, and synaptic plasticity. The Drosophila homolog of CHD7 and CHD8, Kismet (Kis), promotes neurotransmission, endocytosis, and larval locomotion. Endocytosis is essential in neurons for replenishing synaptic vesicles, maintaining protein localization, and preserving the size and composition of the presynaptic membrane. Several forms of endocytosis have been identified including clathrin-mediated endocytosis, which is coupled with neural activity and is the most prevalent form of synaptic endocytosis, and activity-dependent bulk endocytosis, which occurs during periods of intense stimulation. Kis modulates the expression of gene products involved in endocytosis including promoting shaggy/GSK3β expression while restricting PI3K92E. kis mutants electrophysiologically phenocopy a liquid facets mutant in response to paradigms that induce clathrin-mediated endocytosis and activity-dependent bulk endocytosis. Further, kis mutants do not show further reductions in endocytosis when activity-dependent bulk endocytosis or clathrin-mediated endocytosis are pharmacologically inhibited. We find that Kis is important in postsynaptic muscle for proper endocytosis but the ATPase domain of Kis is dispensable for endocytosis. Collectively, our data indicate that Kis promotes both clathrin-mediated endocytosis and activity-dependent bulk endocytosis possibly by promoting transcription of several endocytic genes and maintaining the size of the synaptic vesicle pool.
Topics: Animals; Clathrin; Chromatin; Chromatin Assembly and Disassembly; Synaptic Transmission; Drosophila; Endocytosis; DNA Helicases
PubMed: 38512854
DOI: 10.1371/journal.pone.0300255