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Proceedings of the National Academy of... Dec 1971Evidence has accumulated in recent years for the central role of proteins and enzymes in the function of cell membranes. In the chemical theory proposed for the... (Review)
Review
Evidence has accumulated in recent years for the central role of proteins and enzymes in the function of cell membranes. In the chemical theory proposed for the generation of bioelectricity, i.e., for the control of the ion permeability changes of excitable membranes, the protein assembly associated with the action of acetylcholine plays an essential role. Support of the theory by recent protein studies in which the excitable membranes of the highly specialized electric tissue were used will be discussed. A scheme is presented indicating the possible sequence of chemical reactions that change ion permeability after excitation. A sequence of chemical events within the excitable membranes of the synaptic junctions, i.e., within the pre- and postsynaptic membranes, similar to that proposed for the conducting membranes, is presented in a second scheme as an alternative to the hypothesis of the role of acetylcholine as a transmitter between two cells.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Cell Membrane; Cell Membrane Permeability; Eels; Electric Organ; Electrophysiology; Membrane Potentials; Microscopy, Electron; Neural Conduction; Receptors, Cholinergic; Synaptic Transmission
PubMed: 4332011
DOI: 10.1073/pnas.68.12.3170 -
The Journal of Physiology Nov 2016The functional synaptic connectivity between olfactory receptor neurons and principal cells within the olfactory bulb is not well understood. One view suggests that...
KEY POINTS
The functional synaptic connectivity between olfactory receptor neurons and principal cells within the olfactory bulb is not well understood. One view suggests that mitral cells, the primary output neuron of the olfactory bulb, are solely activated by feedforward excitation. Using focal, single glomerular stimulation, we demonstrate that mitral cells receive direct, monosynaptic input from olfactory receptor neurons. Compared to external tufted cells, mitral cells have a prolonged afferent-evoked EPSC, which serves to amplify the synaptic input. The properties of presynaptic glutamate release from olfactory receptor neurons are similar between mitral and external tufted cells. Our data suggest that afferent input enters the olfactory bulb in a parallel fashion.
ABSTRACT
Primary olfactory receptor neurons terminate in anatomically and functionally discrete cortical modules known as olfactory bulb glomeruli. The synaptic connectivity and postsynaptic responses of mitral and external tufted cells within the glomerulus may involve both direct and indirect components. For example, it has been suggested that sensory input to mitral cells is indirect through feedforward excitation from external tufted cells. We also observed feedforward excitation of mitral cells with weak stimulation of the olfactory nerve layer; however, focal stimulation of an axon bundle entering an individual glomerulus revealed that mitral cells receive monosynaptic afferent inputs. Although external tufted cells had a 4.1-fold larger peak EPSC amplitude, integration of the evoked currents showed that the synaptic charge was 5-fold larger in mitral cells, reflecting the prolonged response in mitral cells. Presynaptic afferents onto mitral and external tufted cells had similar quantal amplitude and release probability, suggesting that the larger peak EPSC in external tufted cells was the result of more synaptic contacts. The results of the present study indicate that the monosynaptic afferent input to mitral cells depends on the strength of odorant stimulation. The enhanced spiking that we observed in response to brief afferent input provides a mechanism for amplifying sensory information and contrasts with the transient response in external tufted cells. These parallel input paths may have discrete functions in processing olfactory sensory input.
Topics: Animals; Electric Stimulation; Excitatory Postsynaptic Potentials; Female; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Neurons, Afferent; Olfactory Bulb; Olfactory Nerve; Olfactory Receptor Neurons; Smell; Synaptic Transmission
PubMed: 27377344
DOI: 10.1113/JP272755 -
The Journal of General Physiology Mar 19571. Recording with glass micropipette electrodes inserted close to the synaptic region, in the presynaptic and in the postsynaptic fibers of the giant synapse in the...
1. Recording with glass micropipette electrodes inserted close to the synaptic region, in the presynaptic and in the postsynaptic fibers of the giant synapse in the stellate ganglion of the squid, has been accomplished. 2. The forms of the spike and of the synaptic potential are very much like those reported earlier (Bullock, 1948) from macroelectrodes. The crest time and the rate of fall are labile and depend on the state of fatigue, though the time of initiation of the postsynaptic potential does not. 3. It is concluded after examination of both intra- and extracellular recordings that there is a real synaptic delay of the order of 1 or 2 milliseconds at 15-20 degrees C. 4. There is sometimes a very small and sometimes no visible deflection in the intracellular postsynaptic record attributable to the presynaptic spike. It is concluded that transmission cannot be electrical. 5. The amplitude of the postsynaptic potential can be controlled over some range by the amplitude of the presynaptic potential. 6. Hyperpolarization of the postsynaptic membrane results in increase in amplitude of spikes up to 200 millivolts, in increase in the membrane potential level at which the spike flares up, but in no considerable change in the amplitude in postsynaptic potential. 7. The postsynaptic potential can add to the late falling phase and the undershoot of an antidromic spike in the postfiber but cannot add to the crest or early part of the falling phase. The earliest part of the antidromic spike during which the postsynaptic potential can add is probably a period of refractoriness to electrical shock by analogy with the properties of the axon.
Topics: Animals; Cytoplasm; Decapodiformes; Membrane Potentials; Synapses; Synaptic Membranes
PubMed: 13416531
DOI: 10.1085/jgp.40.4.565 -
Molecular Psychiatry Jun 2021Homer1 is a synaptic scaffold protein that regulates glutamatergic synapses and spine morphogenesis. HOMER1 knockout (KO) mice show behavioral abnormalities related to...
Homer1 is a synaptic scaffold protein that regulates glutamatergic synapses and spine morphogenesis. HOMER1 knockout (KO) mice show behavioral abnormalities related to psychiatric disorders, and HOMER1 has been associated with psychiatric disorders such as addiction, autism disorder (ASD), schizophrenia (SZ), and depression. However, the mechanisms by which it promotes spine stability and its global function in maintaining the synaptic proteome has not yet been fully investigated. Here, we used computational approaches to identify global functions for proteins containing the Homer1-interacting PPXXF motif within the postsynaptic compartment. Ankyrin-G was one of the most topologically important nodes in the postsynaptic peripheral membrane subnetwork, and we show that one of the PPXXF motifs, present in the postsynaptically-enriched 190 kDa isoform of ankyrin-G (ankyrin-G 190), is recognized by the EVH1 domain of Homer1. We use proximity ligation combined with super-resolution microscopy to map the interaction of ankyrin-G and Homer1 to distinct nanodomains within the spine head and correlate them with spine head size. This interaction motif is critical for ankyrin-G 190's ability to increase spine head size, and for the maintenance of a stable ankyrin-G pool in spines. Intriguingly, lack of Homer1 significantly upregulated the abundance of ankyrin-G, but downregulated Shank3 in cortical crude plasma membrane fractions. In addition, proteomic analysis of the cortex in HOMER1 KO and wild-type (WT) mice revealed a global reshaping of the postsynaptic proteome, surprisingly characterized by extensive upregulation of synaptic proteins. Taken together, we show that Homer1 and its protein interaction motif have broad global functions within synaptic protein-protein interaction networks. Enrichment of disease risk factors within these networks has important implications for neurodevelopmental disorders including bipolar disorder, ASD, and SZ.
Topics: Animals; Ankyrins; Dendritic Spines; Homer Scaffolding Proteins; Mice; Microfilament Proteins; Nerve Tissue Proteins; Proteome; Proteomics; Synapses
PubMed: 33398084
DOI: 10.1038/s41380-020-00991-1 -
Nature Communications Mar 2016Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single...
Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission.
Topics: Animals; Cells, Cultured; Electrophysiological Phenomena; Gene Expression Regulation; HEK293 Cells; Hippocampus; Humans; Membrane Proteins; Mice; Neurons; Rats; Receptors, AMPA; Synapses; Two-Hybrid System Techniques
PubMed: 26931375
DOI: 10.1038/ncomms10682 -
PloS One 2013Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with...
Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin β2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin β2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.
Topics: Acetylcholinesterase; Adolescent; Basement Membrane; Case-Control Studies; Cerebral Palsy; Child; Female; Gene Expression; Humans; Laminin; Male; Membrane Glycoproteins; Microscopy, Electron; Muscle, Skeletal; Nerve Tissue Proteins; Neuromuscular Junction; Prospective Studies; Receptors, Cholinergic; Synapses
PubMed: 23976945
DOI: 10.1371/journal.pone.0070288 -
The Japanese Journal of Physiology Dec 1998Neuron requires a continual supply of materials synthesized in the cell body, for example a wide range of soluble proteins, membranous components, and various... (Review)
Review
Neuron requires a continual supply of materials synthesized in the cell body, for example a wide range of soluble proteins, membranous components, and various organelles. The transported materials are needed to replace constituents that turn over in the membrane and organelles of the fiber and also are needed to bring substances participating in energy metabolism. Other transported components are neurotransmitters or transmitter-related components supplied to the nerve terminals for the release and subsequent excitation of postsynaptic cells. Moreover, neurotropic substances and modulators are released from the nerve terminals to affect the functional state of the neuron. Conversely, some materials are conveyed back to the cell body. These include organelles, lysosomes, nerve growth factor, and selected small molecules such as adenosine, Ca2+, and some neurotransmitters. Axoplasmic transport is thought to be fundamental for a variety of neuronal cell functions. Thus it may be considered that axoplasmic transport relates to the dynamic physiological activity of neurons; in other words, axoplasmic transport is supposed to express the physiological activity of neurons. In turn, as in the case for many other physiological functions, axoplasmic transport is possibly controlled by neuronal, hormonal, and immunological systems. Since axoplasmic transport supplies neuron materials toward the synapses and back to the cell body, a feedback system of regulatory mechanisms of a variety of neuronal functions might be operated through axoplasmic transport pathways. Although axoplasmic transport is the important neuronal function, its regulation is poorly understood. In this review, we focus on the dynamics of organelle transport and its regulatory mechanisms mediated by neurotransmitters.
Topics: Animals; Axonal Transport; Humans; Microscopy, Video; Mitochondria; Models, Biological; Signal Transduction
PubMed: 10021495
DOI: 10.2170/jjphysiol.48.413 -
Journal of Neurochemistry Oct 2006Activity-dependent changes in ionotropic glutamate receptors at the postsynaptic membrane are well established and this regulation plays a central role in the expression...
Activity-dependent changes in ionotropic glutamate receptors at the postsynaptic membrane are well established and this regulation plays a central role in the expression of synaptic plasticity. However, very little is known about the distributions and regulation of ionotropic receptors at presynaptic sites. To determine if presynaptic receptors are subject to similar regulatory processes we investigated the localisation and modulation of AMPA (GluR1, GluR2, GluR3) and kainate (GluR6/7, KA2) receptor subunits by ultrasynaptic separation and immunoblot analysis of rat brain synaptosomes. All of the subunits were enriched in the postsynaptic fraction but were also present in the presynaptic and non-synaptic synaptosome fractions. AMPA stimulation resulted in a marked decrease in postsynaptic GluR2 and GluR3 subunits, but an increase in GluR6/7. Conversely, GluR2 and GluR3 increased in the presynaptic fraction whereas GluR6/7 decreased. There were no significant changes in any of the compartments for GluR1. NMDA treatment decreased postsynaptic GluR1, GluR2 and GluR6/7 but increased presynaptic levels of these subunits. NMDA treatment did not evoke changes in GluR3 localisation. Our results demonstrate that presynaptic and postsynaptic subunits are regulated in opposite directions by AMPA and NMDA stimulation.
Topics: Animals; Brain; Down-Regulation; Excitatory Amino Acid Agonists; Glutamic Acid; Microscopy, Electron, Transmission; N-Methylaspartate; Organ Culture Techniques; Presynaptic Terminals; Protein Subunits; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptosomes; Up-Regulation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 16903873
DOI: 10.1111/j.1471-4159.2006.04087.x -
The Journal of Neuroscience : the... Oct 2006Although prostaglandin E2 (PGE2) has a broad spectrum of biological activities that have been confirmed by previous studies, the roles of PGE2 in synaptic plasticity... (Comparative Study)
Comparative Study
Although prostaglandin E2 (PGE2) has a broad spectrum of biological activities that have been confirmed by previous studies, the roles of PGE2 in synaptic plasticity such as long-term potentiation (LTP) in the CNS have yet to be characterized in detail. The present results of electrophysiological and biochemical studies indicated that PGE2 is actually produced in acute visual cortex slices in response to theta-burst stimulation (TBS) and is involved postsynaptically in TBS-induced LTP. RNA interference (RNAi) for PGE2 receptor subtypes EP2 and EP3, which are known to upregulate and downregulate the level of cAMP, respectively, induced significant decreases and increases of LTP, respectively. Moreover, analysis of the localization of receptor subtypes at the membrane surface or cytosol showed that stimuli such as TBS regulate the trafficking of EP2 and EP3 between the membrane and cytosol of the postsynapses, rising up to and leaving the membrane, respectively, resulting in increased and decreased expression of EP2 and EP3 at the membrane, respectively. Increased activation of EP2 and decreased activation of EP3 by PGE2 synergistically induce an increase in cAMP level, which may induce LTP. This causes activation of CREB (cAMP response element-binding protein) in the postsynaptic cells, which may be involved in the maintenance of LTP. These observations indicate that in TBS-induced LTP of the visual cortex, PGE2 is released from the postsynaptic cells and then activates PGE2 receptors at the postsynaptic membranes, which is regulated by trafficking of the differential PGE2 receptor subtypes in an activity-dependent bidirectional manner.
Topics: Animals; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Long-Term Potentiation; Membrane Proteins; Protein Transport; RNA Interference; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Visual Cortex
PubMed: 17021176
DOI: 10.1523/JNEUROSCI.3028-06.2006 -
Frontiers in Psychiatry 2012THE MULTIPLE ETIOLOGIES OF SCHIZOPHRENIA PROMPT US TO RAISE THE QUESTION: what final common pathway can induce a convincing sense of the reality of the hallucinations in...
THE MULTIPLE ETIOLOGIES OF SCHIZOPHRENIA PROMPT US TO RAISE THE QUESTION: what final common pathway can induce a convincing sense of the reality of the hallucinations in this disease? The observation that artificial stimulation of an intermediate order of neurons of a normal nervous system induces hallucinations indicates that the lateral entry of activity (not resulting from canonical synaptic transmission) at intermediate neuronal orders may provide a mechanism for hallucinations. Meaningful hallucinations can be de-constructed into an organized temporal sequence of internal sensations of associatively learned items that occur in the absence of any external stimuli. We hypothesize that these hallucinations are autonomously generated by the re-activation of pathological non-specific functional LINKs formed between the postsynaptic membranes at certain neuronal orders and are examined as a final common mechanism capable of explaining most of the features of the disease. Reversible and stabilizable hemi-fusion between simultaneously activated adjacent postsynaptic membranes is viewed as one of the normal mechanisms for functional LINK formation and is dependent on lipid membrane composition. Methods of removing the proteins that may traverse the non-specifically hemi-fused membrane segments and attempts to replace the phospholipid side chains to convert the membrane composition to a near-normal state may offer therapeutic opportunities.
PubMed: 23293606
DOI: 10.3389/fpsyt.2012.00108