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The Journal of Neuroscience : the... Aug 2016In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Auditory nerve fibers reflect this tonotopy and encode...
UNLABELLED
In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Auditory nerve fibers reflect this tonotopy and encode temporal properties of acoustic stimuli by "locking" discharges to a particular stimulus phase. However, physiological constraints on phase-locking depend on stimulus frequency. Interestingly, low characteristic frequency (LCF) neurons in the cochlear nucleus improve phase-locking precision relative to their auditory nerve inputs. This is proposed to arise through synaptic integration, but the postsynaptic membrane's selectivity for varying levels of synaptic convergence is poorly understood. The chick cochlear nucleus, nucleus magnocellularis (NM), exhibits tonotopic distribution of both input and membrane properties. LCF neurons receive many small inputs and have low input thresholds, whereas high characteristic frequency (HCF) neurons receive few, large synapses and require larger currents to spike. NM therefore presents an opportunity to study how small membrane variations interact with a systematic topographic gradient of synaptic inputs. We investigated membrane input selectivity and observed that HCF neurons preferentially select faster input than their LCF counterparts, and that this preference is tolerant of changes to membrane voltage. We then used computational models to probe which properties are crucial to phase-locking. The model predicted that the optimal arrangement of synaptic and membrane properties for phase-locking is specific to stimulus frequency and that the tonotopic distribution of input number and membrane excitability in NM closely tracks a stimulus-defined optimum. These findings were then confirmed physiologically with dynamic-clamp simulations of inputs to NM neurons.
SIGNIFICANCE STATEMENT
One way that neurons represent temporal information is by phase-locking, which is discharging in response to a particular phase of the stimulus waveform. In the auditory system, central neurons are optimized to retain or improve phase-locking precision compared with input from the auditory nerve. However, the difficulty of this computation varies systematically with stimulus frequency. We examined properties that contribute to temporal processing both physiologically and in a computational model. Neurons processing low-frequency input benefit from integration of many weak inputs, whereas those processing higher frequencies progressively lose precision by integration of multiple inputs. Here, we reveal general features of input-output optimization that apply to all neurons that process time varying input.
Topics: Action Potentials; Analysis of Variance; Animals; Animals, Newborn; Auditory Pathways; Chick Embryo; Cochlear Nucleus; Computer Simulation; Electric Stimulation; Excitatory Postsynaptic Potentials; In Vitro Techniques; Models, Neurological; Neurons; Patch-Clamp Techniques; Synaptic Transmission
PubMed: 27511020
DOI: 10.1523/JNEUROSCI.4449-15.2016 -
Human Molecular Genetics Jun 2017Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in...
Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength. Collagen XIII is particularly important for the preterminal integrity, and when absent, destabilization of the motor nerves results in muscle regeneration and in atrophy especially in the case of slow muscle fibers. Collagen XIII was found to affect synaptic integrity through binding the ColQ tail of acetylcholine esterase. Although collagen XIII is a muscle-bound transmembrane molecule, it also undergoes ectodomain shedding to become a synaptic basal lamina component. We investigated the two forms' roles by novel Col13a1tm/tm mice in which ectodomain shedding is impaired. While postsynaptic maturation, terminal branching and neurotransmission was exaggerated in the Col13a1tm/tm mice, the transmembrane form's presence sufficed to prevent defects in transsynaptic adhesion, Schwann cell invagination/retraction, vesicle accumulation and acetylcholine receptor clustering and acetylcholinesterase dispersion seen in the Col13a1-/- mice, pointing to the transmembrane form as the major conductor of collagen XIII effects. Altogether, collagen XIII secures postsynaptic, synaptic and presynaptic integrity, and it is required for gaining and maintaining normal size, complexity and functional capacity of the neuromuscular synapse.
Topics: Acetylcholinesterase; Animals; Basement Membrane; Cell Adhesion; Collagen; Collagen Type XIII; Mice; Mice, Knockout; Muscle Proteins; Muscle, Skeletal; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Synapses; Synaptic Transmission
PubMed: 28369367
DOI: 10.1093/hmg/ddx101 -
The Journal of Cell Biology May 1982Synaptosomal plasma membranes were isolated from Torpedo cholinergic synaptosomes which had been purified as previously described or repurified by equilibrium...
Synaptosomal plasma membranes were isolated from Torpedo cholinergic synaptosomes which had been purified as previously described or repurified by equilibrium centrifugation. The synaptosomal plasma membrane could be distinguished from postsynaptic membranes by the absence of postsynaptic specific markers (nicotinic AChR) and by its low intramembrane particle complement after freeze fracture. In addition, the presynaptic membrane fraction contained acetylcholinesterase. Gel electrophoresis permitted the identification of a major protein component of the presynaptic membrane fraction which had a molecular weight of 67,000. This protein was not found in postsynaptic membrane or synaptic vesicle fractions. Thus it appeared to be specific to the nerve terminal plasma membrane.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Cell Fractionation; Cell Membrane; Centrifugation, Density Gradient; Electric Organ; Membrane Proteins; Molecular Weight; Receptors, Cholinergic; Synaptosomes; Torpedo
PubMed: 7096443
DOI: 10.1083/jcb.93.2.349 -
Trends in Pharmacological Sciences Nov 1989Theories of general anesthesia have traditionally been based on correlations between potency and the properties of simple models such as apolar solvents, lipid bilayers... (Review)
Review
Theories of general anesthesia have traditionally been based on correlations between potency and the properties of simple models such as apolar solvents, lipid bilayers and soluble proteins. However, mechanisms can now be determined directly by studying excitable proteins in their membrane environment. Stuart Forman and Keith Miller describe the physiological, biophysical and molecular biological evidence pointing to the location of a discrete allosteric site on the nicotinic acetylcholine receptor at which local anesthetics act. General anesthetics, while superficially resembling local anesthetics in their actions on the receptor, do not appear to act upon such a site.
Topics: Anesthetics; Animals; Humans; Membranes; Receptors, Nicotinic; Synapses
PubMed: 2692257
DOI: 10.1016/S0165-6147(89)80009-4 -
The Journal of General Physiology Nov 1966The ionic mechanism of the electropositive olfactory receptor potential was studied in the bullfrog and the swamp frog. The positive receptor potential strikingly...
The ionic mechanism of the electropositive olfactory receptor potential was studied in the bullfrog and the swamp frog. The positive receptor potential strikingly decreased in amplitude in chloride-free solution. When the olfactory epithelium was immersed in high-KCl-Ringer's solution and then in Cl-free, high-K solution, the polarity of the positive potential could be reversed. This is supposed to be due to the exit of the increased internal chloride ion. From the above two experiments it is concluded that the positive olfactory receptor potential depends primarily upon the influx of the chloride ion through the olfactory receptive membrane. Some contribution by potassium and possibly other ions may occur. The ability of other anions to substitute for chloride was examined. It was found that only Br-, F-, and HCO2- could penetrate the olfactory receptive membrane. The sieve hypothesis in the inhibitory post-synaptic membrane (Coombs, Eccles, and Fatt, 1955) is not applicable to the olfactory receptive membrane on the basis of the size of hydrated ions, but it may be applicable on the basis of the sizes of naked ions.
Topics: Animals; Anions; Bicarbonates; Bromine; Cell Membrane Permeability; Chlorides; Iodine; Membrane Potentials; Olfactory Receptor Neurons; Potassium; Rana catesbeiana; Sulfates
PubMed: 11526841
DOI: 10.1085/jgp.50.2.473 -
The Journal of Neuroscience : the... Feb 1993Synaptic rearrangements in developing muscle were studied by visualizing individual neuromuscular junctions in the sternomastoid muscle of living neonatal mice as they...
Synaptic rearrangements in developing muscle were studied by visualizing individual neuromuscular junctions in the sternomastoid muscle of living neonatal mice as they underwent the transition from multiple to single innervation. Vital staining of ACh receptors (AChRs) with rhodamine-conjugated alpha-bungarotoxin showed that while junctions were still multiply innervated (usually by two motor axons), regions of the postsynaptic membrane within each junction became depleted of receptors. Usually, several small postsynaptic areas lost AChRs in succession. In these areas, AChRs already in the membrane rapidly disappeared compared to a low level of receptor turnover elsewhere in the junction. Moreover, there was no evidence of new AChRs being inserted into these areas. Within each postsynaptic area undergoing AChR depletion, the intensity of receptor staining decreased gradually over 1-2 d. In some junctions, it appeared that AChRs were migrating away from areas being depleted of receptors. The depletion of AChRs from some sites in combination with the spreading apart of the entire receptor-rich area due to muscle fiber growth accounts for the transformation from plaque-like to branched receptor distributions at developing neuromuscular junctions. Vital staining of presynaptic motor nerve terminals at junctions whose postsynaptic AChRs were also stained showed that motor nerve terminals were lost from the same areas that were depleted of receptors postsynaptically. Postsynaptic areas began to be depleted of AChRs before there was any obvious loss of membrane or intracellular staining in the overlying nerve terminal. Only when a single innervating axon remained at a junction did loss of motor nerve terminals and underlying AChRs largely cease. That former synaptic areas could at later times be identified as uninnervated regions within a junction indicates that synapse elimination during development leaves an indelible mark on synaptic structure. These observations suggest that the withdrawal of a motor axon from a neuromuscular junction occurs as a consequence of the stepwise elimination of all of its synapses with that muscle fiber. These results also suggest that an important aspect of synaptic competition leading to axon withdrawal is the precocious loss of AChRs beneath the nerve terminals of the axon that will be eliminated. A similar early loss of AChRs beneath one axon's synapses has been shown to occur during synapse elimination in reinnervated adult muscle (Rich and Lichtman, 1989a).(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Animals, Newborn; Bungarotoxins; Female; Fluorescent Dyes; Male; Mice; Mice, Inbred C57BL; Motor Neurons; Muscle Development; Muscles; Nerve Endings; Neuromuscular Junction; Receptors, Cholinergic; Rhodamines; Synapses
PubMed: 8426240
DOI: 10.1523/JNEUROSCI.13-02-00834.1993 -
Polish Journal of Pharmacology 2000CaM-KII exhibits broad distribution within neurons and discrete localization inside the cell, and it is highly abundant in the postsynaptic densities. The aim of the...
Influence of chronic imipramine administration on the CaM-KII activity in postsynaptic densities and synaptosomal plasma membrane fraction isolated from the rat frontal cortex and hippocampus.
CaM-KII exhibits broad distribution within neurons and discrete localization inside the cell, and it is highly abundant in the postsynaptic densities. The aim of the present study was to investigate the influence of chronic imipramine administration on the CaM-KII activity in postsynaptic densities and synaptosomal plasma membrane fraction isolated from the rat frontal cortex and hippocampus. In the present study, we showed that chronic imipramine administration did not affect the CaM-KII activity localized postsynaptically. Moreover, our results indicated that chronic imipramine treatment evoked a large (300%) increase in CaM-KII activity in synaptosomal plasma membranes fraction isolated from frontal cortex.
Topics: Animals; Antidepressive Agents, Tricyclic; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cell Membrane; Frontal Lobe; Hippocampus; Imipramine; Male; Neurons; Rats; Rats, Wistar; Subcellular Fractions; Synaptosomes
PubMed: 11334242
DOI: No ID Found -
The Journal of General Physiology Oct 1969Reversal potentials (E(IPSP)) of the inhibitory postsynaptic potential and the membrane resting potentials (E(M)) of lobster muscle fibers were determined with...
Reversal potentials (E(IPSP)) of the inhibitory postsynaptic potential and the membrane resting potentials (E(M)) of lobster muscle fibers were determined with intracellular recording under a variety of ionic conditions. E(IPSP) is solely dependent on the electromotive force of anionic batteries; i.e., on the electrochemical gradient for a "mobile" fraction of intracellular Cl (Cl(i)) which is considerably smaller than the total intracellular Cl. The active inhibitory membrane is more permeable to certain "foreign" anions in the order NO(3) > SCN > Br > Cl. The membrane is impermeable to BrO(s), isethionate, and methylsulfate, but is slightly permeable to acetate and propionate. The level of Cl(i) appears to be determined in part by some active (pump?) process and most of the anions studied appear to interfere with the steady-state level of Cl(i).
Topics: Animals; Bromides; Calcium; Cell Membrane Permeability; Chlorides; Crustacea; Electrophysiology; Membranes; Muscles; Neuromuscular Junction; Nitrates; Potassium; Synapses; Synaptic Transmission; Thiocyanates
PubMed: 4309874
DOI: 10.1085/jgp.54.4.437 -
Journal of Neurochemistry May 1994Dystrophin associates with a 58-kDa and an 87-kDa protein in the postsynaptic membrane of the Torpedo electric organ. We have previously shown that the 87-kDa protein is...
Dystrophin associates with a 58-kDa and an 87-kDa protein in the postsynaptic membrane of the Torpedo electric organ. We have previously shown that the 87-kDa protein is a major phosphotyrosine-containing protein in these membranes. Immunoprecipitation of the 87-kDa protein from phosphorylated postsynaptic membranes results in coimmunoprecipitation of additional phosphorproteins. These phosphorproteins are identified as dystrophin and the 58-kDa protein. Monoclonal antibodies to dystrophin and the 58-kDa protein immunoprecipitate phosphorylated forms of these proteins from postsynaptic membranes phosphorylated in vitro. Phosphoamino acid analysis reveals that dystrophin and the 58-kDa protein are phosphorylated on serine and tyrosine residues. In addition, both dystrophin and the 58-kDa protein are shown to be phosphorylated on tyrosine residues in vivo. These results suggest that the synaptic function of dystrophin and its associated proteins, the 58-kDa and 87-kDa proteins, may be modulated by tyrosine and serine protein phosphorylation.
Topics: Adenosine Triphosphate; Animals; Cell Fractionation; Centrifugation, Density Gradient; Dystrophin; Electric Organ; Electrophoresis, Polyacrylamide Gel; Membrane Proteins; Molecular Weight; Phosphoserine; Phosphotyrosine; Synaptic Membranes; Torpedo; Tyrosine
PubMed: 7512621
DOI: 10.1046/j.1471-4159.1994.62051947.x -
Journal of Physiology, Paris 2000The cloning of five members of the somatostatin receptor family, sst1-sst5, as well as two isoforms of the somatostatin receptor 2, sst2A and sst2B, enabled us to... (Review)
Review
The cloning of five members of the somatostatin receptor family, sst1-sst5, as well as two isoforms of the somatostatin receptor 2, sst2A and sst2B, enabled us to generate specific anti-peptide antisera against unique sequences in the carboxyl-terminal tail of each somatostatin receptor subtype. We used these antibodies in multicolor immunofluorescent studies aimed to examine the regional and subcellular distribution of somatostatin receptors in adult rat brain. Several findings are notable: The cloned sst1 receptor is primarily localized to axons, and therefore most likely functions in a presynaptic manner. The cloned sst2 receptor isoforms exhibit strikingly different distributions, however, both sst2A and sst2B are confined to the plasma membrane of neuronal somata and dendrites, and therefore most likely function in a postsynaptic manner. The cloned sst3 receptor appears to be excluded from 'classical' pre- or postsynaptic sites but is selectively targeted to neuronal cilia. The cloned sst4 receptor is preferentially distributed to distal dendrites, and therefore most likely functions postsynaptically. The cloned sst5 receptor was not detectable in the adult rat brain, however, prominent sst5 expression was found in the pituitary. Furthermore, sst1-containing axons either co-contained somatostatin or were closely apposed by somatostatin-positive terminals in a regional-specific manner. Neuronal somata and dendrites containing either sst2A, sst2B or sst4 were found to exist in close proximity, although not necessarily synaptically linked, to somatostatin-positive terminals. Together, in the central nervous system the effects of somatostatin are mediated by several different receptor proteins which are distributed with considerable regional overlap. However, there appears to be a high degree of specialization among somatostatin receptor subtypes with regard to their subcellular targeting. This subtype-selective targeting may be the underlying principal of organization that allows somatostatinergic modulation of neuronal activity via both pre- and postsynaptic mechanisms.
Topics: Animals; Antibody Specificity; Brain Chemistry; Membrane Proteins; Rats; Receptors, Somatostatin
PubMed: 11088003
DOI: 10.1016/s0928-4257(00)00212-6