Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy:

Chronic thiamine deprivation in the rat leads to selective neuropathological damage in brainstem structures whereas treatment with the central thiamine antagonist, pyrithiamine, results in more widespread damage. In order to further elucidate the neurochemical mechanisms responsible for this selective damage, the thiamine-dependent enzyme complex pyruvate dehydrogenase (PDHC) was measured in 10 brain structures in the rat during progression of thiamine deficiency produced by chronic deprivation or by pyrithiamine treatment. Feeding of a thiamine-deficient diet to adult rats resulted in 5–7 weeks in ataxia and loss of righting reflex accompanied by decreased blood transketolase activities. PDHC activities were selectively decreased by 15–30% in midbrain and pons (lateral vestibular nucleus). Thiamine treatment of symptomatic rats led to reversal of neurological signs and to concomitant reductions of the cerebral PDHC abnormalities. Daily pyrithiamine treatment led within 3 weeks to loss of righting reflex and convulsions and to decreased blood transketolase of a comparable magnitude to that observed in chronic thiamine-deprived rats. No significant regional alterations of PDHC, however, were observed in pyrithiamine-treated rats.     

Neurotransmitter function in the basal ganglia after acute and chronic ethanol treatment

Acute and chronic administration of ethanol has multiple effects on several neurotransmitters in the basal ganglia. Dopamine is the transmitter predominantly affected. Acceleration of dopaminergic activity is observed at low doses of ethanol. However, at high doses the reverse is observed. During the ethanol withdrawal syndrome that develops after chronic treatment, dopaminergic responses are reduced, whether from presynaptic or postsynaptic origins. Evidence also indicates that cholinergic and GABAergic processes may be implicated in these actions of ethanol. Ethanol apparently induces a variety of alterations in neurotransmitter function as a result of its disruption of membrane structure and associated electric properties.     

Neurotransmitter transporters in schistosomes: Structure,function and prospects for drug discovery

Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule (“classical”) neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new directions for future research.     

Neurotransmitter release

Axon terminals release more than one physiologically active substance. Synaptic messengers may be stored in two different types of vesicles. Small electron-lucent vesicles mainly store classical low molecular weight transmitter substances and the larger electron-dense granules store and release proteins and peptides. Release of the two types of substances underlies different physiological control. Release of messenger molecules from axon terminals is triggered by influx of Ca2+ through voltage sensitive Ca2+ channels and a rise in cytosolic Ca2+ concentrations. Neither the immediate Ca2+ target(s) nor the molecular species involved in synaptic vesicle docking, fusion and retrieval are known. It is, however, likely that steps involved in the molecular cascade of transmitter release include liberation of vesicles from their association with the cytonet and phosphorylation by protein kinase C of proteins which have the ability to alter between membrane bound and cytoplasmic forms and thus facilitate or initiate the molecular interaction between synaptic vesicles and the plasma membrane.     

Selenium metabolism and selenoproteins function in brain and encephalopathy

Selenium(Se) is an essential trace element of the utmost importance to human health. Its deficiency induces various disorders. Se species can be absorbed by organisms and metabolized to hydrogen selenide for the biosynthesis of selenoproteins, selenonucleic acids, or selenosugars. Se in mammals mainly acts as selenoproteins to exert their biological functions. The brain ranks highest in the specific hierarchy of organs to maintain the level of Se and the expression of selenoproteins under the circumstances of Se deficiency. Dyshomeostasis of Se and dysregulation of selenoproteins result in encephalopathy such as Alzheimer's disease, Parkinson's disease, depression, amyotrophic lateral sclerosis, and multiple sclerosis. This review provides a summary and discussion of Se metabolism, selenoprotein function, and their roles in modulating brain diseases based on the most currently published literature. It focuses on how Se is utilized and transported to the brain,how selenoproteins are biosynthesized and function physiologically in the brain, and how selenoproteins are involved in neurodegenerative diseases. At the end of this review, the perspectives and problems are outlined regarding Se and selenoproteins in the regulation of encephalopathy.     

Neurotransmitter abnormalities in genetically epileptic rodents

A growing body of evidence supports a pathophysiological role for norepinephrine (NE) and serotonin in the regulation of seizures in the genetically epilepsy-prone rat (GEPR). Other evidence indicates that gamma-aminobutyric acid (GABA) and taurine may also participate in the seizure regulation process. Innate deficits in NE and serotonin appear to be causes of the genetically determined seizure-prone states of the GEPR, whereas abnormalities in GABAergic systems and taurine metabolism may represent inadequate attempts of the central nervous system to compensate for the seizure-prone state in these rats. In audiogenic seizure-susceptible (AGS) mice, evidence suggests a role for dopamine as well as GABA and possibly serotonin. NE may contribute to the regulation of seizures in AGS mice, but consistent evidence for a primary role for this monoamine is lacking. It is suggested that there is no single common neurotransmitter abnormality underlying genetic seizure disorders in humans or other animals and that the GEPR and the AGS mouse may both serve as good models for study of the neurochemical abnormalities that underlie the different human epilepsies.     

Bioenergetics of Neurotransmitter Transport

Neurotransmitter transporters are essential components in the recycling of neurotransmitters released during neuronal activity. These transporters are the targets for important drugs affecting mood and behavior. They fall into at least four gene families, two encoding proteins in the plasma membrane and two in the synaptic vesicle membrane, although the known vesicular transporters have not all been cloned. Each of these transporters works by coupling the downhill movement of small ions such as Na⁺, Cl^–, K⁺, and H⁺ to the uphill transport of neurotransmitter. Plasma membrane transporters move the transmitter into the cytoplasm by cotransport with Na⁺. Many transporters also couple Cl^– cotransport to transmitter influx and these all belong to the NaCl-coupled family, although within the family the coupling stoichiometry can vary. Transporters for glutamate couple influx of this excitatory amino acid to Na⁺ and H⁺ influx and K⁺ efflux. Transporters in synaptic vesicles couple H⁺ efflux to neurotransmitter transport from the cytoplasm to the vesicle lumen.     

Neurotransmitter metabolism in murine neuroblastoma cells.

Murine neuroblastoma cells in culture are able to synthesize the putative neurotransmitters--acetylcholine, dopamine, norepinephrine, tyramine, octopamine, histamine, serotonin and γ-aminobutyric acid (GABA). They possess not only synthetic, but also degradative enzymes involved in metabolism of these transmitters, and many of these enzymes increase in activity as the cells “differentiate”. Catecholamines, and perhaps other transmitters, appears to be stored within membrane-limited vesicles which accumulate within the process endings of these cells. Uptake of some transmitters, GABA, glycine, dopamine and norepinephrine, shows characteristics of the high affinity transport systems observed in other neuronal populations; uptake of choline and other amino acids is similar to that in non-neuronal populations. Cells show receptor sensitivities to acetyl-choline, dopamine, norepinephrine, prostaglandins E₁ and morphine, as demonstrated by electrophysiologic, toxin binding and cyclic nucleotide studies.     

Neurotransmitter receptor alterations in Parkinson's disease.

Neurotransmitter receptor binding for GABA, serotonin, cholinergic muscarinic and dopamine receptors and choline acetyltransferase (ChAc) activity were measured in the frontal cortex, caudate nucleus, putamen and globus pallidus from postmortem brains of 10 Parkinsonian patients and 10 controls. No changes in any of these systems were observed in the frontal cortex. In the caudaye nucleus, only the apparent dopamine receptor binding was altered with a significant 30% decrease in the Parkinsonian brain. Both cholinergic muscarinic and serotonin receptor binding were significantly altered in the putamen, the former increasing and the latter decreasing with respect to controls. In addition, ChAc activity was decreased in the putamen. In the globus pallidus, only ChAc activity was significantly changed, decreasing about 60%, with no change in neurotransmitter receptor binding. The results suggest that a progressive loss of dopaminergic receptors in the caudate nucleus may contribute to the decreased response of Parkinsonian patients to L-dopa and dopamine agonist therapy.     

Gene-Based Neurotransmitter Modulation in Cerebellar Granule Neurons

Abstract: The human glutamic acid decarboxylase (GAD) gene was transferred into rat cerebellar granule neurons. Following adenoviral-mediated gene transfer, nearly 100% of the neurons had transgene expression that persisted for the duration of their survival in culture. GABA levels were elevated both in the growth media and in lysates of GAD-modified granule neurons. In GAD-modified neurons, extracellular GABA levels steadily increased with time, whereas intracellular GABA levels peaked 10 days after gene transfer. GAD-modified neurons released both glutamate and GABA into the surrounding media before and after potassium-induced stimulation, but only the release of glutamate was sensitive to potassium stimulation. These data suggest that glutamatergic neurons, which initially contained no detectable GABA, can be genetically modified to release GABA constitutively.     

Neurotransmitter control of pupillary motoricity in man

The pupillary responses to different agonists and antagonists of the sympathetic and parasympathetic systems have been studied in normal volunteers. The eyedrops were instilled unilaterally and the responses were evaluated by measuring the changes in diameter of the pupils (in millimeters). All the eyedrops induced an unilateral response on the instilled side. The mydriatic substances (phenylephrine, thropamide, tyramine) showed an evident and lasting action. Phenylephrine 1% was found to be a threshold dose to acquire the mydriatic effect. The beta blocking agent (timolol) induced a short mydriatic response, while methaproterenol did not change the pupillary diameter. Clonidine caused an unilateral mydriasis. The alpha blocking agent and the parasympathetic system stimulation agent induced miotic effects The results are discussed with particular reference to the possible mechanism of the pupillary response to timolol and clonidine.     

Epinephrine: A Potential Neurotransmitter in Retina

Abstract: Dopamine (DA), norepinephrine (NE), and epinephrine (EPI) are present in rat retina. DA is the major catecholamine, whereas NE and EPI represent ∼5% of the DA content. DA is contained in a subpopulation of amacrine cells and has been the subject of numerous studies. We investigated the origin and properties of NE and EPI in retina. Following superior cervical ganglionectomy, there was a decrease in NE content, but no decrease in EPI or phenylethanolamine- N -methyltransferase (PNMT) activity. PNMT in retina has many of the substrate-specificity and inhibitor-sensitivity characteristics of other tissues. Enzyme activity is enhanced in newborn rats by treatment with dexamethasone. Exposure to a lighted environment increases retinal EPI in normal and superior cervical ganglionectomized rats. EPI content increased for more than 2 h in a lighted environment. We conclude that most of the NE is contained within the sympathetic neurons that innervate the eye from the superior cervical ganglion, whereas EPI is contained in retinal elements that are responsive to photic stimulation.     

Neurotransmitter release mechanisms studied in Caenorhabditis elegans

The process of regulated exocytosis has received considerable interest as a key component of synaptic transmission. Fusion of presynaptic vesicles and the subsequent release of their neurotransmitter contents is driven by a series of interactions between evolutionarily conserved proteins. Key insights into the molecular mechanisms of vesicle fusion have come from research using genetic model systems such as the nematode worm Caenorhabditis elegans. We review here the current knowledge regarding regulated exocytosis at the C. elegans synapse and future research directions involving this model organism.     

Neurotransmitter release at central synapses

Our understanding of synaptic transmission has grown dramatically during the 15 years since the first issue of Neuron was published, a growth rate expected from the rapid progress in modern biology. As in all of biology, new techniques have led to major advances in the cell and molecular biology of synapses, and the subject has evolved in ways (like the production of genetically engineered mice) that could not even be imagined 15 years ago. My plan for this review is to summarize what we knew about neurotransmitter release when Neuron first appeared and what we recognized we did not know, and then to describe how our views have changed in the intervening decade and a half. Some things we knew about synapses--"knew" in the sense that the field had reached a consensus--are no longer accepted, but for the most part, impressive advances have led to a new consensus on many issues. What I find fascinating is that in certain ways nothing has changed--many of the old arguments persist or recur in a different guise--but in other ways the field would be unrecognizable to a neurobiologist time-transported from 1988 to 2003.     

Neurotransmitter release at rapid synapses

The classical concept of the vesicular hypothesis for acetylcholine (ACh) release, one quantum resulting from exocytosis of one vesicle, is becoming more complicated than initially thought. 1) synaptic vesicles do contain ACh, but the cytoplasmic pool of ACh is the first to be used and renewed on stimulation. 2) The vesicles store not only ACh, but also ATP and Ca(2+) and they are critically involved in determining the local Ca(2+) microdomains which trigger and control release. 3) The number of exocytosis pits does increase in the membrane upon nerve stimulation, but in most cases exocytosis happens after the precise time of release, while it is a change affecting intramembrane particles which reflects more faithfully the release kinetics. 4) The SNARE proteins, which dock vesicles close to Ca(2+) channels, are essential for the excitation-release coupling, but quantal release persists when the SNAREs are inactivated or absent. 5) The quantum size is identical at the neuromuscular and nerve-electroplaque junctions, but the volume of a synaptic vesicle is eight times larger in electric organ; at this synapse there is enough ACh in a single vesicle to generate 15-25 large quanta, or 150-200 subquanta. These contradictions may be only apparent and can be resolved if one takes into account that an integral plasmalemmal protein can support the formation of ACh quanta. Such a protein has been isolated, characterised and called mediatophore. Mediatophore has been localised at the active zones of presynaptic nerve terminals. It is able to release ACh with the expected Ca(2+)-dependency and quantal character, as demonstrated using mediatophore-transfected cells and other reconstituted systems. Mediatophore is believed to work like a pore protein, the regulation of which is in turn likely to depend on the SNARE-vesicle docking apparatus.     

Neurotransmitter system markers in adult barrel field

Abstract

Purpose: Skin contributes to joint position sense (JPS) at multiple joints. Altered cutaneous input at the foot can modulate gait and balance and kinesiology tape can enhance proprioception at the knee, but its effect may be dependent on existing capacity. The effect of texture at the knee, particularly in those with poor proprioception, is unknown. The aim of this study was to determine the effect of textured panels on JPS about the knee.

Materials and methods: Eighteen healthy females were seated in an adjustable chair. Their left leg (target limb) moved passively from 65° to a target of flexion (115° or 90°) or extension (40°). Their right leg (matching limb) was passively moved towards this target angle and participants indicated when their limbs felt aligned. We tested three textured panels over the knee of the matching limb and two control conditions. The target limb maintained a control panel. Directional error, absolute error and variable error in matching between limbs were calculated.

Results: On average textured panels over the knee increased JPS error compared to control pants for participants with poor JPS. These participants undershot the target at 90° of flexion significantly more with textured panels (?11°?±?3°) versus control (?7°?±?3°, p?=?0.04).

Conclusions: For participants with poor JPS accuracy, increased JPS error at 90° with a textured panel suggests these individuals utilised altered cutaneous information to adjust joint position. We propose increased error results from enhanced skin input at the knee leading to the perception of increased flexion.