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Biophysical Reviews Apr 2024This Commentary presents a brief discussion of the action of glutamate calcium permeable receptors present with neurons on the release of the neurotransmitter... (Review)
Review
This Commentary presents a brief discussion of the action of glutamate calcium permeable receptors present with neurons on the release of the neurotransmitter gamma-aminobutyric acid (GABA). In particular, Glutamate sensitive Kainic Acid Receptors (KARs) and α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptor (AMPARs) are Na channels that typically cause neuronal cells to depolarize and release GABA. Some of these receptors are also permeable to Ca and are hence involved in the calcium-dependent release of GABA neurotransmitters. Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs) are predominantly located in GABAergic neurons in the mature brain and their primary role is to regulate GABA release. AMPARs which do not contain the GluA2 subunit are mainly localized in the postsynaptic membrane. CP-KAR receptors are located mainly in the presynapse. GABAergic neurons expressing CP-KARs and CP-AMPARs respond to excitation earlier and faster, suppressing hyperexcitation of other neurons by the advanced GABA release due to an early rapid [Ca] increase. CP-AMPARs have demonstrated a more pronounced impact on plasticity compared to NMDARs because of their capacity to elevate intracellular Ca levels independently of voltage. GABAergic neurons that express CP-AMPARs contribute to the disinhibition of glutamatergic neurons by suppressing GABAergic neurons that express CP-KARs. Hence, the presence of glutamate CP-KARs and CP-AMPARs is crucial in governing hyperexcitation and synaptic plasticity in GABAergic neurons.
PubMed: 38737208
DOI: 10.1007/s12551-024-01184-8 -
Molecules (Basel, Switzerland) Apr 2024Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion...
Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound -tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs' active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.
Topics: Molecular Docking Simulation; Neuromuscular Blocking Agents; Receptors, Nicotinic; Humans; Molecular Dynamics Simulation; Drug Discovery; Protein Binding; Binding Sites; Ligands
PubMed: 38731447
DOI: 10.3390/molecules29091955 -
The European Physical Journal. E, Soft... May 2024The aggregation or clustering of proteins and other macromolecules plays an important role in the formation of large-scale molecular assemblies within cell membranes....
The aggregation or clustering of proteins and other macromolecules plays an important role in the formation of large-scale molecular assemblies within cell membranes. Examples of such assemblies include lipid rafts, and postsynaptic domains (PSDs) at excitatory and inhibitory synapses in neurons. PSDs are rich in scaffolding proteins that can transiently trap transmembrane neurotransmitter receptors, thus localizing them at specific spatial positions. Hence, PSDs play a key role in determining the strength of synaptic connections and their regulation during learning and memory. Recently, a two-dimensional (2D) diffusion-mediated aggregation model of PSD formation has been developed in which the spatial locations of the clusters are determined by a set of fixed anchoring sites. The system is kept out of equilibrium by the recycling of particles between the cell membrane and interior. This results in a stationary distribution consisting of multiple clusters, whose average size can be determined using an effective mean-field description of the particle concentration around each anchored cluster. In this paper, we derive corrections to the mean-field approximation by applying the theory of diffusion in singularly perturbed domains. The latter is a powerful analytical method for solving two-dimensional (2D) and three-dimensional (3D) diffusion problems in domains where small holes or perforations have been removed from the interior. Applications range from modeling intracellular diffusion, where interior holes could represent subcellular structures such as organelles or biological condensates, to tracking the spread of chemical pollutants or heat from localized sources. In this paper, we take the bounded domain to be the cell membrane and the holes to represent anchored clusters. The analysis proceeds by partitioning the membrane into a set of inner regions around each cluster, and an outer region where mean-field interactions occur. Asymptotically matching the inner and outer stationary solutions generates an asymptotic expansion of the particle concentration, which includes higher-order corrections to mean-field theory that depend on the positions of the clusters and the boundary of the domain. Motivated by a recent study of light-activated protein oligomerization in cells, we also develop the analogous theory for cluster formation in a three-dimensional (3D) domain. The details of the asymptotic analysis differ from the 2D case due to the contrasting singularity structure of 2D and 3D Green's functions.
Topics: Diffusion; Cell Membrane; Membrane Microdomains; Models, Biological
PubMed: 38720027
DOI: 10.1140/epje/s10189-024-00425-8 -
BioRxiv : the Preprint Server For... Apr 2024Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by...
Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extra-sensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in Dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) projecting CT neurons located in lower L6a than VPm-only projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements.
PubMed: 38712153
DOI: 10.1101/2024.04.22.590613 -
Small Methods May 2024Memristor possesses great potential and advantages in neuromorphic computing, while consistency and power consumption issues have been hindering its commercialization....
Memristor possesses great potential and advantages in neuromorphic computing, while consistency and power consumption issues have been hindering its commercialization. Low cost and accuracy are the advantages of human brain, so memristors can be used to construct brain-like synaptic devices to solve these problems. In this work, a five-layer AlO device with a V-shaped oxygen distribution is used to simulate biological synapses. The device simulates synapse structurally. Further, under electrical stimulation, O moves to the Ti electrode and oxygen vacancy (V) moves to the Pt electrode, thus forming a conductive filament (CF), which simulates the Ca flow and releases neurotransmitters to the postsynaptic membrane, thus realizing the transmission of information. By controlling applied voltage, the regulation of Ca gated pathway is realized to control the Ca internal flow and achieve different degrees of information transmission. Long-term Potentiation (LTP)/Long-term Depression (LTD), Spike Timing Dependent Plasticity (STDP), these basic synaptic performances can be simulated. The AlO device realizes low power consumption (56.7 pJ/392 fJ), high switching speed (25 ns/60 ns), and by adjusting the window value, the nonlinearity is improved (0.133/0.084), a high recognition accuracy (98.18%) is obtained in neuromorphic simulation. It shows a great prospect in multi-value storage and neuromorphic computing.
PubMed: 38708670
DOI: 10.1002/smtd.202301657 -
Cerebral Cortex (New York, N.Y. : 1991) May 2024Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier...
Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.
Topics: Prefrontal Cortex; Humans; Male; Female; Synapses; Adult; Middle Aged; Autism Spectrum Disorder; Young Adult; Adolescent; Child; Autistic Disorder; Neural Inhibition; Vesicular Glutamate Transport Protein 1; Membrane Proteins
PubMed: 38696601
DOI: 10.1093/cercor/bhad268 -
PloS One 2024Although behavioural defensive responses have been recorded several times in both laboratory and natural habitats, their neural mechanisms have seldom been investigated....
Although behavioural defensive responses have been recorded several times in both laboratory and natural habitats, their neural mechanisms have seldom been investigated. To explore how chemical, water-borne cues are conveyed to the forebrain and instruct behavioural responses in anuran larvae, we conditioned newly hatched agile frog tadpoles using predator olfactory cues, specifically either native odonate larvae or alien crayfish kairomones. We expected chronic treatments to influence the basal neuronal activity of the tadpoles' mitral cells and alter their sensory neuronal connections, thereby impacting information processing. Subsequently, these neurons were acutely perfused, and their responses were compared with the defensive behaviour of tadpoles previously conditioned and exposed to the same cues. Tadpoles conditioned with odonate cues differed in both passive and active cell properties compared to those exposed to water (controls) or crayfish cues. The observed upregulation of membrane conductance and increase in both the number of active synapses and receptor density at the postsynaptic site are believed to have enhanced their responsiveness to external stimuli. Odonate cues also affected the resting membrane potential and firing rate of mitral cells during electrophysiological patch-clamp recordings, suggesting a rearrangement of the repertoire of voltage-dependent conductances expressed in cell membranes. These recorded neural changes may modulate the induction of an action potential and transmission of information. Furthermore, the recording of neural activity indicated that the lack of defensive responses towards non-native predators is due to the non-recognition of their olfactory cues.
Topics: Animals; Larva; Predatory Behavior; Cues; Anura; Olfactory Receptor Neurons; Astacoidea
PubMed: 38696517
DOI: 10.1371/journal.pone.0302728 -
Animal Cells and Systems 2024Parkinson's disease (PD) often results in hippocampal dysfunction, which leads to cognitive and emotional challenges and synaptic irregularities. This study attempted to...
Parkinson's disease (PD) often results in hippocampal dysfunction, which leads to cognitive and emotional challenges and synaptic irregularities. This study attempted to assess behavioral anomalies and identify differentially expressed genes (DEGs) within the hippocampus of a hemiparkinsonian rat model to potentially uncover novel genetic candidates linked to hippocampal dysfunction. Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in the brains of adult SD rats, while dopaminergic impairments were verified in rats with 6-OHDA-lesioned striata. RNA sequencing and gene expression analysis unveiled 1018 DEGs in the ipsilateral rat hippocampus following 6-OHDA infusion: 631 genes exhibited upregulation, while 387 genes were downregulated (with FDR-adjusted -value < 0.05 and absolute fold-change > 1.5). Gene ontology analysis of DEGs indicated that alterations in the hippocampi of 6-OHDA-lesioned rats were primarily associated with synaptic signaling, axon development, behavior, postsynaptic membrane, synaptic membrane, neurotransmitter receptor activity, and peptide receptor activity. The Kyoto Encyclopedia of Genes and Genomes analysis of DEGs demonstrated significant enrichment of the neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, axon guidance, and notch signaling pathway in rat hippocampi that had been subjected to striatal 6-OHDA infusion. STRING analysis confirmed a notable upregulation of eight hub genes (, , , , , , , and ), along with a significant downregulation of two hub genes ( and ), as validated by reverse transcription-quantitative polymerase chain reaction. This study provides a comprehensive transcriptomic profile of the hippocampi in a hemiparkinsonian rat model, thereby offering insights into the signaling pathways underlying hippocampal dysfunction.
PubMed: 38693920
DOI: 10.1080/19768354.2024.2348671 -
BioEssays : News and Reviews in... Jul 2024Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP,... (Review)
Review
Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA-type glutamate receptors (AMPARs). A combination of AMPAR structural data, super-resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever-clearer picture of how AMPARs are recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse.
Topics: Receptors, AMPA; Animals; Humans; Synapses; Long-Term Potentiation; Synaptic Transmission; CA1 Region, Hippocampal
PubMed: 38693811
DOI: 10.1002/bies.202400006 -
Pesticide Biochemistry and Physiology May 2024Pyridine alkylsulfone derivatives typified by oxazosulfyl (Sumitomo Chemical Company Ltd.) and compound A2 (Syngenta) represent a new class of insecticides, with potent...
Pyridine alkylsulfone derivatives typified by oxazosulfyl (Sumitomo Chemical Company Ltd.) and compound A2 (Syngenta) represent a new class of insecticides, with potent activity against several insect orders. Whilst the MOA of this class has been attributed to interaction with the voltage-gated sodium channel (VGSC), here we present strong evidence that their toxicity to insects is mediated primarily through inhibition of the vesicular acetylcholine transporter (VAChT). Alkylsulfone intoxication in insects is characterised by (i) a reduction in cholinergic synaptic transmission efficiency demonstrated by a depression of cercal afferent activity in giant-interneurone preparations of American cockroach (Periplaneta americana), (ii) selective block of cholinergic-transmission dependent post-synaptic potentials in the Drosophila giant-fibre pathway and (iii) abolition of miniature excitatory post-synaptic currents (mEPSCs) in an identified synapse in Drosophila larvae. Ligand-binding studies using a tritiated example compound ([H]-A1) revealed a single saturable binding-site, with low nanomolar K value, in membrane fractions of green bottle fly (Lucilia sericata). Binding is inhibited by vesamicol and by several examples of a previously identified class of insecticidal compounds known to target VAChT, the spiroindolines. Displacement of this binding by analogues of the radioligand reveals a strong correlation with insecticidal potency. No specific binding was detected in untransformed PC12 cells but a PC12 line stably expressing Drosophila VAChT showed similar affinity for [H]-A1 as that seen in fly head membrane preparations. Previously identified VAChT point mutations confer resistance to the spiroindoline class of insecticides in Drosophila by Gal-4/UAS directed expression in cholinergic neurones and by CRISPR gene-editing of VAChT, but none of these flies show detectable cross-resistance to this new chemical class. Oxazosulfyl was previously shown to stabilise voltage-gated sodium channels in their slow-inactivated conformation with an IC value of 12.3μM but inhibits binding of [H]-A1 with approximately 5000 times greater potency. We believe this chemistry class represents a novel mode-of-action with high potential for invertebrate selectivity.
Topics: Animals; Insecticides; Sulfones; Drosophila; Periplaneta; Synaptic Transmission; Acetylcholine
PubMed: 38685234
DOI: 10.1016/j.pestbp.2024.105854