A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gai... more A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice. The functional analysis showed a consistent delay in the propagation of the action potential in mutant mice in comparison with control littermates. Morphological analyses of glial cells in motor axons revealed signs of compact myelin damage as tomacula and local hypermyelination foci. Moreover, we observed an alteration in non-myelinated terminal Schwann cells at the level of the NMJ. Additionally, we found a significant increment of phosphorylated Akt-2 in the sciatic n...
Cysteine string protein (CSP) is an abundant synaptic vesicle protein that contains a DNA-J domai... more Cysteine string protein (CSP) is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSP in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSP deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSP-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP, thereby accounting for the lack of a hair-cell phenotype in CSP knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration. hair cell | ribbon synapse | electroretinogram | chaperone | blindness
Nocturnal rise in pineal melatonin output is due to the night-induced acceleration of noradrenerg... more Nocturnal rise in pineal melatonin output is due to the night-induced acceleration of noradrenergic transmission and alpha(1)- and beta-adrenoceptor activation. In addition, in female animals, cyclic oscillations in circulating levels of sex steroid hormones are accompanied by changes in the rate of pineal melatonin secretion. To investigate whether estrogen directly affects pineal adrenoceptor responsiveness, pinealocytes from 21-day-old ovariectomized rats were exposed to physiological concentrations of 17beta-estradiol (17beta-E(2)) and treated with noradrenergic agonists. Direct exposure to 17beta-E(2) reduced alpha(1)/beta-adrenoceptor-induced stimulation of melatonin synthesis and release. This effect was mediated by an estrogen-dependent inhibition of both beta-adrenoceptor-induced accumulation of cAMP and alpha(1)-adrenoceptor-induced phosphoinositide hydrolysis. Furthermore, estrogen reduced transient Ca(2+) signals elicited in single pinealocytes by alpha(1)-adrenoceptor a...
Steroid hormones may affect, simultaneously, a wide variety of neuronal targets and influence the... more Steroid hormones may affect, simultaneously, a wide variety of neuronal targets and influence the way neural networks interact and the way the brain reacts to the environment. Some of the neuronal effects of steroid hormones may be very fast and affect specific membrane conductances or second messenger cascades, while others may last a long time and exert profound influences on
Exocytosis, the fusion of secretory vesicles with the plasma membrane to allow release of the con... more Exocytosis, the fusion of secretory vesicles with the plasma membrane to allow release of the contents of the vesicles into the extracellular environment, and endocytosis, the internalization of these vesicles to allow another round of secretion, are coupled. It is, however, uncertain whether exocytosis and endocytosis are tightly coupled, such that secretory vesicles fuse only transiently with the plasma membrane before being internalized (the 'kiss-and-run' mechanism), or whether endocytosis occurs by an independent process following complete incorporation of the secretory vesicle into the plasma membrane. Here we investigate the fate of single secretory vesicles after fusion with the plasma membrane by measuring capacitance changes and transmitter release in rat chromaffin cells using the cell-attached patch-amperometry technique. We show that raised concentrations of extracellular calcium ions shift the preferred mode of exocytosis to the kiss-and-run mechanism in a calc...
A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gai... more A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice. The functional analysis showed a consistent delay in the propagation of the action potential in mutant mice in comparison with control littermates. Morphological analyses of glial cells in motor axons revealed signs of compact myelin damage as tomacula and local hypermyelination foci. Moreover, we observed an alteration in non-myelinated terminal Schwann cells at the level of the NMJ. Additionally, we found a significant increment of phosphorylated Akt-2 in the sciatic n...
Cysteine string protein (CSP) is an abundant synaptic vesicle protein that contains a DNA-J domai... more Cysteine string protein (CSP) is an abundant synaptic vesicle protein that contains a DNA-J domain characteristic of Hsp40-type cochaperones. Previous studies showed that deletion of CSP in mice leads to massive lethal neurodegeneration but did not clarify how the neurodegeneration affects specific subpopulations of neurons. Here, we analyzed the effects of the CSP deficiency on tonically active ribbon synapses of the retina and the inner ear. We show that CSP-deficient photoreceptor terminals undergo dramatic and rapidly progressive neurodegeneration that starts before eye opening and initially does not affect other retinal synapses. These changes are associated with progressive blindness. In contrast, ribbon synapses of auditory hair cells did not exhibit presynaptic impairments in CSP-deficient mice. Hair cells, but not photoreceptor cells or central neurons, express CSP, thereby accounting for the lack of a hair-cell phenotype in CSP knockout mice. Our data demonstrate that tonically active ribbon synapses in retina are particularly sensitive to the deletion of CSP and that expression of at least one CSP isoform is essential to protect such tonically active synapses from neurodegeneration. hair cell | ribbon synapse | electroretinogram | chaperone | blindness
Nocturnal rise in pineal melatonin output is due to the night-induced acceleration of noradrenerg... more Nocturnal rise in pineal melatonin output is due to the night-induced acceleration of noradrenergic transmission and alpha(1)- and beta-adrenoceptor activation. In addition, in female animals, cyclic oscillations in circulating levels of sex steroid hormones are accompanied by changes in the rate of pineal melatonin secretion. To investigate whether estrogen directly affects pineal adrenoceptor responsiveness, pinealocytes from 21-day-old ovariectomized rats were exposed to physiological concentrations of 17beta-estradiol (17beta-E(2)) and treated with noradrenergic agonists. Direct exposure to 17beta-E(2) reduced alpha(1)/beta-adrenoceptor-induced stimulation of melatonin synthesis and release. This effect was mediated by an estrogen-dependent inhibition of both beta-adrenoceptor-induced accumulation of cAMP and alpha(1)-adrenoceptor-induced phosphoinositide hydrolysis. Furthermore, estrogen reduced transient Ca(2+) signals elicited in single pinealocytes by alpha(1)-adrenoceptor a...
Steroid hormones may affect, simultaneously, a wide variety of neuronal targets and influence the... more Steroid hormones may affect, simultaneously, a wide variety of neuronal targets and influence the way neural networks interact and the way the brain reacts to the environment. Some of the neuronal effects of steroid hormones may be very fast and affect specific membrane conductances or second messenger cascades, while others may last a long time and exert profound influences on
Exocytosis, the fusion of secretory vesicles with the plasma membrane to allow release of the con... more Exocytosis, the fusion of secretory vesicles with the plasma membrane to allow release of the contents of the vesicles into the extracellular environment, and endocytosis, the internalization of these vesicles to allow another round of secretion, are coupled. It is, however, uncertain whether exocytosis and endocytosis are tightly coupled, such that secretory vesicles fuse only transiently with the plasma membrane before being internalized (the 'kiss-and-run' mechanism), or whether endocytosis occurs by an independent process following complete incorporation of the secretory vesicle into the plasma membrane. Here we investigate the fate of single secretory vesicles after fusion with the plasma membrane by measuring capacitance changes and transmitter release in rat chromaffin cells using the cell-attached patch-amperometry technique. We show that raised concentrations of extracellular calcium ions shift the preferred mode of exocytosis to the kiss-and-run mechanism in a calc...
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Papers by Lucia Tabares