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Neuropharmacology Aug 2023Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in...
Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15-P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABA receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development.
Topics: Animals; Mice; Acceleration; Chlorides; gamma-Aminobutyric Acid; Membrane Transport Proteins; Receptors, GABA-A; Symporters; Stress, Physiological
PubMed: 37061088
DOI: 10.1016/j.neuropharm.2023.109543 -
Neuron Nov 1999Postsynaptic density 95 (PSD-95/SAP-90) is a membrane associated guanylate kinase (GK) PDZ protein that scaffolds glutamate receptors and associated signaling networks...
Postsynaptic density 95 (PSD-95/SAP-90) is a membrane associated guanylate kinase (GK) PDZ protein that scaffolds glutamate receptors and associated signaling networks at excitatory synapses. Affinity chromatography identifies cypin as a major PSD-95-binding protein in brain extracts. Cypin is homologous to a family of hydrolytic bacterial enzymes and shares some similarity with collapsin response mediator protein (CRMP), a cytoplasmic mediator of semaphorin III signalling. Cypin is discretely expressed in neurons and is polarized to basal membranes in intestinal epithelial cells. Overexpression of cypin in hippocampal neurons specifically perturbs postsynaptic trafficking of PSD-95 and SAP-102, an effect not produced by overexpression of other PDZ ligands. In fact, PSD-95 can induce postsynaptic clustering of an otherwise diffusely localized K+ channel, Kv1.4. By regulating postsynaptic protein sorting, cypin may influence synaptic development and plasticity.
Topics: Amino Acid Sequence; Animals; Binding Sites; Brain; Carrier Proteins; Cerebral Cortex; Chemical Fractionation; Cytosol; Disks Large Homolog 4 Protein; Guanine Deaminase; Guanylate Kinases; Intestinal Mucosa; Intracellular Membranes; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Molecular Sequence Data; Nerve Tissue Proteins; Neurons; Nucleoside-Phosphate Kinase; Presynaptic Terminals; Rats; Synapses
PubMed: 10595517
DOI: 10.1016/s0896-6273(00)81120-4 -
Philosophical Transactions of the Royal... Mar 1991Agrin, a protein isolated from the synapse-rich electric organ of Torpedo californica, induces the formation of specializations on myotubes in culture which resemble the... (Review)
Review
Agrin, a protein isolated from the synapse-rich electric organ of Torpedo californica, induces the formation of specializations on myotubes in culture which resemble the post-synaptic apparatus at the vertebrate skeletal neuromuscular junction. For example, the specializations contain aggregates of acetylcholine receptors and acetylcholinesterase. This report summarizes the evidence that the formation of the post-synaptic apparatus at developing and regenerating neuromuscular junctions is triggered by the release of agrin from motor axon terminals and describes results of recent experiments which suggest that agrin-induced tyrosine phosphorylation of the beta subunit of the acetylcholine receptor may play a role in receptor aggregation.
Topics: Agrin; Animals; Basement Membrane; Models, Neurological; Motor Neurons; Muscles; Nerve Tissue Proteins; Phosphorylation; Protein-Tyrosine Kinases; Receptors, Cholinergic; Synapses
PubMed: 1677470
DOI: 10.1098/rstb.1991.0016 -
Italian Journal of Anatomy and... 2008Microtunbule-depolymerizing agents cause amnesia. Some signal translocations to the stimulated postsynaptic membrane are essential for inducing LTP in CA1 neurons like... (Review)
Review
Microtunbule-depolymerizing agents cause amnesia. Some signal translocations to the stimulated postsynaptic membrane are essential for inducing LTP in CA1 neurons like AMPA receptors, CaMKII and mRNA. On the other hand, LTP requires protein synthesis and gene expression. This indicates that signals generated at the synapse might be transmitted to the nucleus. Recently, we have reported that LTP-producing stimulation makes new microtubule track between cell body and the stimulated postsynaptic membrane in CA1 neurons. This newly produced microtubule track only to the stimulated postsynaptic membrane might be the route of these bi-directional transportation of signals during LTP formation. This lead us the hypothesis of the "endless memory amplifying circuit" that means gene expression-promoting molecules are translocated from postsynaptic membrane to the cell body and enter into nucleus and activate transcription factors, and gene products, which will probably promote plasticity, may be re-translocated only to the stimulated postsynaptic membrane along microtubules.
Topics: Animals; Gene Expression Regulation; Hippocampus; Humans; Long-Term Potentiation; Memory; Microtubules; Neural Pathways; Neurons; Protein Transport; Signal Transduction; Synaptic Membranes
PubMed: 19507463
DOI: No ID Found -
Cell and Tissue Research Mar 2003The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two... (Review)
Review
The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two major inhibitory neurotransmitters. They can be released independently from different terminals or co-released from the same terminal to activate postsynaptic glycine and GABA(A) receptors. The anchoring protein gephyrin is involved in the postsynaptic accumulation of both glycine and GABA(A) receptors. In lower brain regions, both receptors can be concentrated in synapses, whereas in higher brain regions, glycine receptors are mostly excluded from postsynaptic sites. The activation of glycine and/or GABA(A) receptors determines the strength and precise timing of inhibition. Therefore, tight regulation of postsynaptic glycine versus GABA(A) receptor localization is crucial for optimizing synaptic inhibition in neurons. This review focuses on recent findings and discusses questions concerning the specificity of postsynaptic inhibitory neurotransmitter receptor accumulation during inhibitory synapse formation and development.
Topics: Animals; Brain; Carrier Proteins; Humans; Membrane Proteins; Neural Inhibition; Receptors, GABA-A; Receptors, Glycine; Receptors, Neurotransmitter; Synaptic Membranes; Synaptic Transmission
PubMed: 12658435
DOI: 10.1007/s00441-002-0694-9 -
Neuroscience Letters Mar 1996Intramembranous structure of the postsynaptic membrane of the axodendritic synapses in the rat sensorimotor cortex was examined by means of freeze-etching technique....
Intramembranous structure of the postsynaptic membrane of the axodendritic synapses in the rat sensorimotor cortex was examined by means of freeze-etching technique. Perforated and non-perforated aggregates of particles were found at the extracellular half (E-face) of the postsynaptic membrane. To study correlation between membrane structure and synaptic plasticity we compared size and particle packing density in both type aggregates of particles at the E-face of the postsynaptic dendritic spine membrane. The results are discussed in terms of plasticity on the synaptic contact zone (SCZ) at the postsynaptic membrane of the excitatory axospinous synapses.
Topics: Animals; Dendrites; Neuronal Plasticity; Rats; Rats, Wistar; Somatosensory Cortex; Synaptic Membranes
PubMed: 8710168
DOI: 10.1016/s0304-3940(96)12443-5 -
The Journal of Membrane Biology 1975Electron-microscope autoradiography of diaphragm endplates of the American brown bat, labeled to saturation with tritiated alpha-bungarotoxin, has been used as a means...
Electron-microscope autoradiography of diaphragm endplates of the American brown bat, labeled to saturation with tritiated alpha-bungarotoxin, has been used as a means to localize and quantitate the acetylcholine receptor there. Analysis of the grain distribution in these autoradiographs reveals that the receptor sites in this endplate are located on the postsynaptic membrane at an average density of 8,800/mu2. The sites are distributed asymmetrically along that membrane, being concentrated at the crests of the postjunctional folds--that portion nearest to the presynaptic membrane. The receptor site density at these regions of the postsynaptic membrane is estimated to be 20,000--25,000/mu2 of membrane surface. A comparison of these membrane site densities with those of endplates of red and white fibers of the mouse reveals a close similarity. On this basis, it is suggested that the receptor site density at the crests of the folds may be a characteristic feature of endplates of vertebrates. In contrast to the acetylcholine receptor sites, cholinesterase sites (determined autoradiographically in 3H-diisopropylfluorophosphate-labeled endplates) are largely distributed in a uniform manner over the postjunctional folds. The function of the secondary folds is, therefore, reassessed. Ultrastructural evidence available from other laboratories on the spatial characteristics of transmitter release and of postsynaptic dense particles is in accord with a model drawn for this molecular architecture at the vertebrate endplate.
Topics: Animals; Binding Sites; Bungarotoxins; Chiroptera; Diaphragm; Isoflurophate; Membranes; Mice; Microscopy, Electron; Motor Endplate; Muscle, Smooth; Neuromuscular Junction; Receptors, Cholinergic; Species Specificity
PubMed: 1121027
DOI: 10.1007/BF01870626 -
Neuroscience and Biobehavioral Reviews 1983One of the many actions of ethanol involves the GABAergic system. The interaction of ethanol with GABAergic neurons is a complex one involving both presynaptic and... (Review)
Review
One of the many actions of ethanol involves the GABAergic system. The interaction of ethanol with GABAergic neurons is a complex one involving both presynaptic and postsynaptic sites. Through a presumed fluidization of membranes after a single dose of ethanol, the available in vitro evidence suggests that ethanol disrupts the normal functioning of the GABA-benzodiazepine-chloride ionophore complex in a complicated manner involving a sequential activation of different active sites leading to the facilitation of GABA transmission. This finding has been supported in vivo using electrophysiological techniques. Presynaptic GABAergic neurons may experience a reduced activity, especially at low doses of ethanol. After chronic ethanol treatment, GABAergic transmission may be reduced, especially during an ethanol withdrawal syndrome. Also, other changes in the GABA-benzodiazepine-chloride ionophore complex suggest GABA transmission is suppressed postsynaptically. Drugs which enhance the actions of GABA may be suitable inhibitors of the ethanol withdrawal syndrome. In particular a new class of drugs, the triazolopyridazines, may be promising compounds for treatment of withdrawal with a more specific mode of action and fewer side effects.
Topics: Alcohol Withdrawal Delirium; Alcoholism; Animals; Anti-Anxiety Agents; Benzodiazepines; Brain; Dose-Response Relationship, Drug; Ethanol; Humans; Neurons; Receptors, Cell Surface; Receptors, GABA-A; Synapses; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 6132358
DOI: 10.1016/0149-7634(83)90009-x -
Journal of Neurocytology 2003Fast chemical synapses are comprised of presynaptic and postsynaptic specializations precisely aligned across a protein-filled synaptic cleft. At the vertebrate... (Review)
Review
Fast chemical synapses are comprised of presynaptic and postsynaptic specializations precisely aligned across a protein-filled synaptic cleft. At the vertebrate neuromuscular junction (NMJ), the synaptic cleft contains a structured form of extracellular matrix known as a basal lamina (BL). Synaptic BL is molecularly differentiated from the BL that covers the extrasynaptic region of the myofiber. This review summarizes current understanding of the morphology, composition, and function of the synaptic BL at the vertebrate NMJ. Considerable evidence supports the conclusion that the synaptic BL organizes and maintains pre- and postsynaptic specializations during development and regeneration, and promotes robust neurotransmission in the adult.
Topics: Animals; Basement Membrane; Humans; Membrane Proteins; Neuromuscular Junction; Synapses
PubMed: 15034274
DOI: 10.1023/B:NEUR.0000020630.74955.19 -
Sleep Jan 2015Hypoglossal motoneurons were recorded intracellularly to determine whether postsynaptic inhibition or disfacilitation was responsible for atonia of the lingual muscles...
STUDY OBJECTIVES
Hypoglossal motoneurons were recorded intracellularly to determine whether postsynaptic inhibition or disfacilitation was responsible for atonia of the lingual muscles during rapid eye movement (REM) sleep.
DESIGN
Intracellular records were obtained of the action potentials and subthreshold membrane potential activity of antidromically identified hypoglossal motoneurons in cats during wakefulness, nonrapid eye movement (NREM) sleep, and REM sleep. A cuff electrode was placed around the hypoglossal nerve to antidromically activate hypoglossal motoneurons. The state-dependent changes in membrane potential, spontaneous discharge, postsynaptic potentials, and rheobase of hypoglossal motoneurons were determined.
ANALYSES AND RESULTS
During quiet wakefulness and NREM sleep, hypoglossal motoneurons exhibited spontaneous repetitive discharge. In the transition from NREM sleep to REM sleep, repetitive discharge ceased and the membrane potential began to hyperpolarize; maximal hyperpolarization (10.5 mV) persisted throughout REM sleep. During REM sleep there was a significant increase in rheobase, which was accompanied by barrages of large-amplitude inhibitory postsynaptic potentials (IPSPs), which were reversed following the intracellular injection of chloride ions. The latter result indicates that they were mediated by glycine; IPSPs were not present during wakefulness or NREM sleep.
CONCLUSIONS
We conclude that hypoglossal motoneurons are postsynaptically inhibited during naturally occurring REM sleep; no evidence of disfacilitation was observed. The data also indicate that glycine receptor-mediated postsynaptic inhibition of hypoglossal motoneurons is crucial in promoting atonia of the lingual muscles during REM sleep.
Topics: Animals; Cats; Chlorides; Electric Stimulation; Hypoglossal Nerve; Inhibitory Postsynaptic Potentials; Male; Membrane Potentials; Motor Neurons; Muscle Hypotonia; Muscles; Receptors, Glycine; Sleep, REM; Tongue; Wakefulness
PubMed: 25325470
DOI: 10.5665/sleep.4340