[Elements concerning the cellular organization of glycine receptors dependent of chlorine].
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Glycine is one of the main inhibitory neurotransmitter in the central nervous system of vertebrates where it acts by activating a chloride conductance. The distribution of glycine receptor at the neuronal surface was analysed by immunocytochemistry with monoclonal antibodies raised against the purified receptor. In the rat spinal cord as well as in other areas of the central nervous system, these receptors are localized at the postsynaptic membrane and are concentrated in front of the presynaptic release sites. Thus, they define functional microdomains at the plasma membrane. A similar organisation was observed in a motor command neuron: the Mauthner cell of Teleosts. Further, in this model, a quantitative analysis using confocal microscopy has established that the postsynaptic microdomains are arranged according to a somatodendritic gradient with the larger clusters at the tip of the dendrites. The use of primary cultures of rat or mouse spinal cord neurons has allowed to study the ontogenesis of the glycine receptor. We have shown that these receptors are, here also, organized in clusters present at the neuronal surface and that the formation of these aggregates occurs simultaneously to the establishment of synaptic contacts.Keywords:
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Glycine is one of the main inhibitory neurotransmitter in the central nervous system of vertebrates where it acts by activating a chloride conductance. The distribution of glycine receptor at the neuronal surface was analysed by immunocytochemistry with monoclonal antibodies raised against the purified receptor. In the rat spinal cord as well as in other areas of the central nervous system, these receptors are localized at the postsynaptic membrane and are concentrated in front of the presynaptic release sites. Thus, they define functional microdomains at the plasma membrane. A similar organisation was observed in a motor command neuron: the Mauthner cell of Teleosts. Further, in this model, a quantitative analysis using confocal microscopy has established that the postsynaptic microdomains are arranged according to a somatodendritic gradient with the larger clusters at the tip of the dendrites. The use of primary cultures of rat or mouse spinal cord neurons has allowed to study the ontogenesis of the glycine receptor. We have shown that these receptors are, here also, organized in clusters present at the neuronal surface and that the formation of these aggregates occurs simultaneously to the establishment of synaptic contacts.
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Immunocytochemistry allows for a precise localization of neurotransmitter receptors in tissues and cells. This review summarizes much of the available data on the cellular and subcellular distribution of serotonin (5-hydroxytryptamine [5-HT]) receptors in the mammalian central nervous system. Among fourteen 5-HT receptor types, all cloned and sequenced, only a few have yet been amenable to detailed immunocytochemical visualization, not only at the light microscopic but particularly at the electron microscopic level. The 5-HT1A and 5-HT2A receptors have been the most thoroughly investigated and provide a meaningful demonstration of the wealth of information to be gained from this methodological approach, not only in terms of anatomical and cytological localization, and thus physiological role and eventual implication in health and disease, but also of functional properties and drug effects.
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After some words on the scientific role of Professor Paolo Mantegazza atthe University of Milan (4, 5, 6), I briefly illustrate some studies related to the occurrence of neurotransmitter and receptor re-specification in the adult animals. The greatdiscoveries of the early twentieth century on neuronal communication have established that the majority of communication between nerve cells occurs through a special structure, the synapse, allowing the one-way transfer of information between twocells through the release of a neurotransmitter from the presynaptic cell and its recognition by receptors localized in the postsynaptic cell. According to H. Dale axiom (9) each neuron could be identified on the basis of the neurotransmitter released and theinnervated cell by the type of receptors expressed; then neurons could be classified asexcitatory if they release acetylcholine, glutamate or other transmitters, or inhibitory ifthey release GABA or glycine. However, in recent years many studies have shown that, especially during development, a neuron could release and co-release several neuro-transmitters, sometimes even simultaneously, changing its classification from excitatory to inhibitory and vice versa(7). This researches opened a new field of study onsynaptic plasticity: the neurotransmitter and receptor re-specification. Our group, together with Prof. Mantegazza, tried to “force†it through experiments of denervation and heterologous re-innervation in the autonomic nervous system and at the neuromuscular junction. In a first series of experiments we studied the regenerative capabilities of the peripheral nervous system in three experimental models: a) re-innervation of the denervated superior cervical ganglion (SCG) (14, 15, 22) by cholinergicefferent vagal fibers, b) re-innervation of peripheral effectors smooth muscles (nicti-tating membrane) by the cholinergic preganglionic fibers; c) re-innervation in an in vivo transplant model of peripheral organs by the SCG. In these researches we haveestablished: 1) that a sympathetic ganglion could be re-innervated by vagal fibersforming normal ganglionic synapses, but with a strong reshaping, in vivo, of the cen-tral neural circuits so that sympathetic stimuli occurred through a vagal excitation; 2) preganglionic cholinergic fibers innervate the smooth muscle of the nictitating mem-brane releasing catecholamines instead of acetylcholine; 3) that in an in vivo model ofSCG transplant together with iris or adrenal medulla fragments, the SCG was able todistinguish between organs that required a postsynaptic innervation, iris, which wasinnervated, and organs that require a presynaptic innervation, the adrenal medulla,that was not innervated. We were then in the presence, even in the adult animal, of anew nervous plasticity with re-specification the neurotransmitter. These resultsdemonstrate that heterologous innervation could “force†plasticity in adult peripheralnervous system, alters the biological properties of neurons, upsets central neuronal circuits, but continues to maintain in experimental transplants basic rules of innervation between neurons and peripheral organs. Thirty years later, the group of prof. Brunelliin Brescia (23), along with pharmacologists and physiologists, had highlighted the pos-sibility of re-innervate striated muscles in a functional way with nerve fibers derivedfrom the red nucleus of the vestibular complex. The interest was, once again, in thefact that the re-innervating fibers were of glutamatergic type, and not cholinergic likethose of normal motor neurons, and that neuromuscular transmission was transformedfrom nicotinic cholinergic in glutamatergic. A new type of plasticity: the receptor re-specification had occurred also in this experimenal model. In close cooperationbetween our Milan and the Brescia group we could reconfirm with more appropriateexperiments that the re-innervation occurred; that neuromuscular junction had a glutamatergic transmission; that new re-innervating fibers made synapses at the same sitesof the previous neuromuscular junctions; that the new fibers release glutamate; andthat muscle cells expressed new glutamate receptors (24). Once again we were in thepresence of an extraordinary phenomenon of synaptic plasticity, in this case a receptorre-specification, and again with a strong impact on the central nervous system circuits.These experiences, along with many others now available in the literature, show thatthe adult peripheral nervous system, both autonomous and musculoskeletal, has aplasticity unthinkable before and open a field of great interest aiming at the understanding how neuronal specificity is regulated and at the investigation of non-canonical, but perhaps functional, re-innervation experiments in transplants and in post-traumatic surgery.
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Abstract This chapter discusses the modalities of information transfer in the nervous system. The nervous system is organised around specialised cells called neurons, which work as integration units that transform all received information into new information. The neurons generate unitary electric pulses of invariant form and duration called action potentials or spikes. Neurons have an intrinsic firing frequency that is their frequency of producing spikes when they are not influenced. The chapter then considers the two major families of neurotransmitters. In general, a neuron releases only one type of neurotransmitter belonging to one of these two families. The first family is that of excitatory neurotransmitters; the neurons that release them are naturally called excitatory neurons. When they bind with postsynaptic receptors, they have a facilitating effect on the production of action potentials. Meanwhile, inhibitory neurons release neurotransmitters whose binding with postsynaptic receptors decreases the discharge frequency of the postsynaptic neuron. The chapter also describes a special family of neurotransmitters: the neuro-modulators.
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Size and shape of glycine receptor clusters in a central neuron exhibit a somato-dendritic gradient.
The overall surface disposition of receptors for the neurotransmitter glycine was examined in situ on the teleost Mauthner cell. For this purpose, a monoclonal antibody specific for the glycine receptor was used in immunofluorescence experiments in association with the technique of confocal microscopy. Previous work had shown that on the Mauthner cell and other neurons, receptors for this transmitter are concentrated in discrete microdomains apposed to single presynaptic terminals. We now report that the size and the shape of these clusters depend on their cellular location, that is, their area increases regularly from the soma to the tip of the dendrites. Conversely, the number of clusters per unit area declines so that the final proportion of immunoreactive membrane remains constant at any portion of the cell. These results raise the question of the functional consequences of such an organized subcellular distribution of receptors.
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Gamma-aminobutyric acid (GABA) is one of the principle inhibitory neurotransmitters in the mature spinal cord. It effectively suppresses synaptic transmission by mechanisms of postsynaptic and presynaptic inhibition. The function of GABA is less well understood early in spinal cord development, when the amino acid is transiently expressed in most neurons, and it depolarizes instead of hyperpolarizes neurons. This article reviews the possible physiological roles of GABA in modulating synaptic transmission, promoting neuronal development, and regulating neuronal pH during early stages of spinal cord differentiation. It is proposed that despite its depolarizing action, GABA acts as an inhibitory neurotransmitter that may also function as a neurotrophic agent.
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Abstract Neurons, building blocks of the mammalian nervous system, mainly communicate with each other through synapses in which signal transmission is mediated by neurotransmitters released from the presynaptic neuron and sensed by the postsynaptic neuron. These endogenous chemicals released from the nerve terminal diffuse through the very narrow extracellular space between the neurons and bind to specific membrane proteins called receptors, thereby mediating signal propagation. Receptors are divided into two large families comprising those causing the activation of second messengers and those including an ionic pore which opens upon neurotransmitter binding and which controls flow of ions across the cell membrane. Also called ligand‐gated ion channels (LGIC), they mediate fast neurotransmission essential for the complex signal processing in the central nervous system. Reliable transmission of signals between neurons is highly dependent on accurate functioning of LGICs. Genetically transmissible nervous system disorders can be caused by mutations in genes coding for LGICs, resulting in dramatically altered neurotransmission. Key Concepts In this work we review the determinant role of ligand gated ion channels in brain function and the alterations related to genetic variants.
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Over the last several years our knowledge of neurotransmitter receptors has increased dramatically as receptor types and subtypes have been identified through the development of selective antagonists, neuropharmacological studies, and radioactive ligand binding studies. At the same time major advances were made in the immunocytochemical localization of neurotransmitters and their related enzymes. However, only recently has immunocytochemistry been used to localize neurotransmitter receptors, and these studies have been limited. Four receptors have been localized in the CNS with immunocytochemistry: the nicotinic acetylcholine receptor, the beta-adrenergic receptor, the GABA/benzodiazepine receptor, and the glycine receptor. Of these the glycine receptor has been the most thoroughly characterized. Glycine receptor immunoreactivity is highly concentrated at postsynaptic sites, and the distribution of immunoreactivity appears to correlate closely with glycinergic neurons. However, immunocytochemical studies done on other receptors suggest such a distribution may not always be the case. Some receptors may not be concentrated at postsynaptic sites, and receptor distribution may not always closely fit the distribution of the respective neurotransmitter. Work is rapidly progressing on the purification of other receptors and on the production of selective antibodies which will allow immunocytochemical studies which address these and other questions.
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Gephyrin
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