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Biomedical subjects

T Moser

Publications and source records attributed to T Moser.

At least 19 recordsLinked to original sources
PubMed2006

Synaptic organization in cochlear inner hair cells deficient for the CaV1.3 (alpha1D) subunit of L-type Ca2+ channels.

Cochlear inner hair cells (IHCs) release neurotransmitter onto afferent auditory nerve fibers in response to sound stimulation. Normal development and function of inner hair cells require the expression of alpha subunit 1.3 forming L-type voltage-gated Ca(2+) channel (Ca(V)1.3). Here, we used immunohistochemistry and reverse transcription-polymerase chain reaction to study the synaptic organization and expression of large conductance Ca(2+)-activated potassium channels in IHCs of mice lacking the Ca(V)1.3 Ca(2+) channel (Ca(V)1.3(-/-)). Despite the near complete block of evoked afferent synaptic transmission, hair cell ribbon synapses were formed and remained preserved for at least 4 weeks after birth. Moreover, these "silent" afferent synapses held major components of the synaptic machinery such as Bassoon, Piccolo, and CSP. Hence, the block of exocytosis might be solely attributed to the lack of Ca(2+) influx through Ca(V)1.3 channels. Later on, Ca(V)1.3 deficient IHCs subsequently lost their afferent synapses. This was probably due to a secondary degeneration of the postsynaptic spiral ganglion neurons. In line with a prolonged efferent synaptic transmission onto Ca(V)1.3 deficient IHCs, which normally ceases around onset of hearing, we found juxtaposed immunoreactive spots of efferent presynaptic synaptophysin and postsynaptic (IHCs) small conductance Ca(2+)-activated potassium channels (SK channels) up to six weeks after birth. Finally, we show a substantial reduction of mRNA for the alpha subunit of the large conductance Ca(2+)-activated potassium channel (BK) in the apical cochlea, suggesting a reduced transcription of its gene in Ca(V)1.3 deficient IHCs. Ca(V)1.3 deficient IHCs lacked the apical spot-like immunoreactivity of clustered BK channels, which normally contribute to the temporal precision of hair cell afferent synaptic transmission. In summary, these data indicate that the Ca(V)1.3 channels are crucially involved in regulation of the expression of BK and SK channels. Ca(V)1.3 channels seem not to be essential for ribbon synapse formation, but are required for the maintenance of ribbon synapses and spiral ganglion neurons.

Age Factors↗
PubMed2006

Structure and function of the hair cell ribbon synapse.

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse--the electron-dense synaptic ribbon or synaptic body--has been recognized for decades, dissection of the synapse's molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years.

Afferent Pathways↗
PubMed2006

Decrease of thalamic gray matter following limb amputation.

Modern neuroscience has elucidated general mechanisms underlying the functional plasticity of the adult mammalian brain after limb deafferentation. However, little is known about possible structural alterations following amputation and chronic loss of afferent input in humans. Using voxel-based morphometry (VBM), based on high-resolution magnetic resonance images, we investigated the brain structure of 28 volunteers with unilateral limb amputation and compared them to healthy controls. Subjects with limb amputation exhibited a decrease in gray matter of the posterolateral thalamus contralateral to the side of the amputation. The thalamic gray matter differences were positively correlated with the time span after the amputation but not with the frequency or magnitude of coexisting phantom pain. Phantom limb pain was unrelated to thalamic structural variations, but was positively correlated to a decrease in brain areas related to the processing of pain. No gray matter increase was detected. The unilateral thalamic differences may reflect a structural correlate of the loss of afferent input as a secondary change following deafferentation.

Adolescent↗
PubMed2006

alpha-Neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction.

Neurotransmission at chemical synapses of the brain involves alpha-neurexins, neuron-specific cell-surface molecules that are encoded by three genes in mammals. Deletion of alpha-neurexins in mice previously demonstrated an essential function, leading to early postnatal death of many double-knockout mice and all triple mutants. Neurotransmitter release at central synapses of newborn knockouts was severely reduced, a function of alpha-neurexins that requires their extracellular sequences. Here, we investigated the role of alpha-neurexins at neuromuscular junctions, presynaptic terminals that lack a neuronal postsynaptic partner, addressing an important question because the function of neurexins was hypothesized to involve cell-adhesion complexes between neurons. Using systems physiology, morphological analyses and electrophysiological recordings, we show that quantal content, i.e. the number of acetylcholine quanta released per nerve impulse from motor nerve terminals, and frequency of spontaneous miniature endplate potentials at the slow-twitch soleus muscle are reduced in adult alpha-neurexin double-knockouts, consistent with earlier data on central synapses. However, the same parameters at diaphragm muscle neuromuscular junctions showed no difference in basal neurotransmission. To reconcile these observations, we tested the capability of control and alpha-neurexin-deficient diaphragm neuromuscular junctions to compensate for an experimental reduction of postsynaptic acetylcholine receptors by a compensatory increase of presynaptic release: Knockout neuromuscular junctions produced significantly less upregulation of quantal content than synapses from control mice. Our data suggest that alpha-neurexins are required for efficient neurotransmitter release at neuromuscular junctions, and that they may perform a role in the molecular mechanism of synaptic homeostasis at these peripheral synapses.

Animals↗
PubMed2006

[Diagnosis and therapy of auditory synaptopathy/neuropathy].

Pathological auditory brainstem responses (lack of responses, elevated thresholds and perturbed waveforms) in combination with present otoacoustic emissions are typical audiometric findings in patients with a hearing impairment that particularly affects speech comprehension or complete deafness. This heterogenous group of disorders first described as "auditory neuropathy" includes dysfunction of peripheral synaptic coding of sound by inner hair cells (synaptopathy) and/or of the generation and propagation of action potentials in the auditory nerve (neuropathy). This joint statement provides prevailing background information as well as recommendations on diagnosis and treatment. The statement focuses on the handling in the german language area but also refers to current international statements.

Brain Stem↗
PubMed2006

Root canal system in the mesiobuccal root of the maxillary first molar: an in vitro comparison study of computed tomography and histology.

OBJECTIVES: The purpose of this study was to investigate a new diagnostic approach to the examination of the canal configuration of the mesiobuccal root of the maxillary first molar. MATERIALS AND METHODS: High-resolution computed tomography (CT) was compared with histology in vitro. There were 152 teeth investigated and classified according to Weine and Vertucci. RESULTS: CT describes the exact canal configuration, verifying information identical to histology, and thus serving as the "gold standard" in vitro. With regard to canal position, 9 (5.92%) of the teeth examined were Vertucci type 1, 48 (31.58%) were Vertucci type 2, 91 (59.87%) were Vertucci type 4, 1 (0.66%) was Vertucci type 5, 1 (0.66%) was Vertucci type 6. Of the 152 teeth examined, 3 (1.97%) could not be classified using Weine, 2 (1.31%) could not be classified according to either Weine or Vertucci, and no Vertucci types 3, 7 or 8 were identified. CONCLUSIONS: CT offers complete information on the number and configuration of root canals. As the root canal configuration of the adult does not change rapidly, CT investigations can be used for multiple subsequent treatments.

Adult↗
PubMed2005

[Primary meningeal intermediate grade melanocytic neoplasm: case report with radiologic-pathologic correlation].

A case of primary meningeal intermediate grade melanocytic neoplasm involving the right C2 nerve root is presented. MRI findings may suggest this rare entity, especially when an extra-axial lesion is located in the posterior fossa or cervical spinal canal and demonstrates shortening of both T1 and T2. Eventually, definitive diagnosis relies on histology which demonstrates spindle-shaped melanocytic cells that are Fontana stained and positive for HMB:45 antigen. Cellularity, pleomorphism, mitotic rate, proliferation index and invasiveness are useful criteria to distinguish among the spectrum of primary melanocytic tumors of the central nervous system ranging from melanocytoma to malignant melanoma.

Adult↗
PubMed2001

Intracellular calcium dependence of large dense-core vesicle exocytosis in the absence of synaptotagmin I.

Synaptotagmin I is a synaptic vesicle-associated protein essential for synchronous neurotransmission. We investigated its impact on the intracellular Ca(2+)-dependence of large dense-core vesicle (LDCV) exocytosis by combining Ca(2+)-uncaging and membrane capacitance measurements in adrenal slices from mouse synaptotagmin I null mutants. Synaptotagmin I-deficient chromaffin cells displayed prolonged exocytic delays and slow, yet Ca(2+)-dependent fusion rates, resulting in strongly reduced LDCV release in response to short depolarizations. Vesicle recruitment, the shape of individual amperometric events, and endocytosis appeared unaffected. These findings demonstrate that synaptotagmin I is required for rapid, highly Ca(2+)-sensitive LDCV exocytosis and indicate that it regulates the equilibrium between a slowly releasable and a readily releasable state of the fusion machinery. Alternatively, synaptotagmin I could function as calcium sensor for the readily releasable pool, leading to the destabilization of the pool in its absence.

Adrenal Glands↗
PubMed2001

Munc18-1 promotes large dense-core vesicle docking.

Secretory vesicles dock at the plasma membrane before Ca(2+) triggers their exocytosis. Exocytosis requires the assembly of SNARE complexes formed by the vesicle protein Synaptobrevin and the membrane proteins Syntaxin-1 and SNAP-25. We analyzed the role of Munc18-1, a cytosolic binding partner of Syntaxin-1, in large dense-core vesicle (LDCV) secretion. Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls. Concomitantly, mutant cells displayed a 10-fold reduction in morphologically docked LDCVs. Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply. We conclude that Munc18-1 functions upstream of SNARE complex formation and promotes LDCV docking.

Animals↗
PubMed2001

The presynaptic function of mouse cochlear inner hair cells during development of hearing.

Before mice start to hear at approximately postnatal day 10, their cochlear inner hair cells (IHCs) spontaneously generate Ca(2+) action potentials. Therefore, immature IHCs could stimulate the auditory pathway, provided that they were already competent for transmitter release. Here, we combined patch-clamp capacitance measurements and fluorimetric [Ca(2+)](i) recordings to study the presynaptic function of IHCs during cochlear maturation. Ca(2+)-dependent exocytosis and subsequent endocytic membrane retrieval were already observed near the date of birth. Ca(2+) action potentials triggered exocytosis in immature IHCs, which probably activates the auditory pathway before it becomes responsive to sound. IHCs underwent profound changes in Ca(2+)-channel expression and secretion during their postnatal development. Ca(2+)-channel expression increased toward the end of the first week, providing for large secretory responses during this period and thereafter declined to reach mature levels. The efficacy whereby Ca(2+) influx triggers exocytosis increased toward maturation, such that vesicle fusion caused by a given Ca(2+) current occurred faster in mature IHCs. The observed changes in Ca(2+)-channel expression and synaptic efficacy probably reflected the ongoing synaptogenesis in IHCs that had been described previously in morphological studies.

Action Potentials↗
PubMed2001

Calcium dependence of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse.

Release of neurotransmitter at the inner hair cell (IHC) afferent synapse is a fundamental step in translating sound into auditory nerve excitation. To study the Ca2+ dependence of the underlying vesicle fusion and subsequent endocytosis, we combined Ca2+ uncaging with membrane capacitance measurements in mouse IHCs. Rapid elevations in [Ca2+]i above 8 microM caused a biphasic capacitance increase corresponding to the fusion of approximately 40,000 vesicles. The kinetics of exocytosis displayed a fifth-order Ca2+ dependence reaching maximal rates of >3 x 10(7) vesicle/s. Exocytosis was always followed by slow, compensatory endocytosis (tau congruent with 15 s). Higher [Ca2+]i increased the contribution of a faster mode of endocytosis with a Ca2+ independent time constant of approximately 300 ms. These properties provide for rapid and sustained transmitter release from this large presynaptic terminal.

Animals↗
PubMed2000

R-Type Ca2+ channels are coupled to the rapid component of secretion in mouse adrenal slice chromaffin cells.

Patch-clamp measurements of Ca(2+) currents and membrane capacitance were performed on slices of mouse adrenal glands, using the perforated-patch configuration of the patch-clamp technique. These recording conditions are much closer to the in vivo situation than those used so far in most electrophysiological studies in adrenal chromaffin cells (isolated cells maintained in culture and whole-cell configuration). We observed profound discrepancies in the quantities of Ca(2+) channel subtypes (P-, Q-, N-, and L-type Ca(2+) channels) described for isolated mouse chromaffin cells maintained in culture. Differences with respect to previous studies may be attributable not only to culture conditions, but also to the patch-clamp configuration used. Our experiments revealed the presence of a Ca(2+) channel subtype never before described in chromaffin cells, a toxin and dihydropyridine-resistant Ca(2+) channel with fast inactivation kinetics, similar to the R-type Ca(2+) channel described in neurons. This channel contributes 22% to the total Ca(2+) current and controls 55% of the rapid secretory response evoked by short depolarizing pulses. Our results indicate that R-type Ca(2+) channels are in close proximity with the exocytotic machinery to rapidly regulate the secretory process.

Adrenal Glands↗
PubMed2000

The readily releasable pool of vesicles in chromaffin cells is replenished in a temperature-dependent manner and transiently overfills at 37 degrees C.

Maturation of exocytic vesicles to the release-ready state is regulated by several factors, including intracellular calcium concentration ([Ca(2+)](int)) and the state of protein phosphorylation. Here we investigated the effects of temperature on the recovery from depletion of the readily releasable pool (RRP) of vesicles in adrenal chromaffin cells. Exocytosis and [Ca(2+)](int) were monitored by combined membrane capacitance and fura-2 measurements. At higher temperatures, a faster pool refilling and a larger RRP size were observed. The time constants of the recovery from depletion ranged from 3.6 to 1.1 sec (22 and 37 degrees C, respectively) yielding a Q(10) of 2.3. The changes of the Ca(2+) signal between the different temperatures could not account for the differences in recovery kinetics. At 32 and 37 degrees C, we observed a transient overfilling of the RRP after pool depletion, which stands in clear contrast to the sustained secretory depression seen at lower temperatures. The overshoot in RRP size was very prominent in cells with lower basal [Ca(2+)](int), hence with a large difference between prestimulus and poststimulus [Ca(2+)](int). In cells with higher basal [Ca(2+)](int), the pool was larger under steady-state conditions but showed less overfilling on stimulation. We conclude that vesicle maturation is markedly accelerated at physiological temperature, thus allowing for a rapid adaptation of the pool size to the relatively short-lived Ca(2+) transient.

Animals↗
PubMed2000

Kinetics of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse of the mouse.

Hearing in mammals relies on the highly synchronous synaptic transfer between cochlear inner hair cells (IHCs) and the auditory nerve. We studied the presynaptic function of single mouse IHCs by monitoring membrane capacitance changes and voltage-gated Ca(2+) currents. Exocytosis initially occurred at a high rate but then slowed down within a few milliseconds, despite nearly constant Ca(2+) influx. We interpret the observed secretory depression as depletion of a readily releasable pool (RRP) of about 280 vesicles. These vesicles are probably docked close to Ca(2+) channels at the ribbon-type active zones of the IHCs. Continued depolarization evoked slower exocytosis occurring at a nearly constant rate for at least 1 s and depending on "long-distance" Ca(2+) signaling. Refilling of the RRP after depletion followed a biphasic time course and was faster than endocytosis. RRP depletion is discussed as a mechanism for fast auditory adaptation.

Animals↗
PubMed1999

Mechanisms underlying phasic and sustained secretion in chromaffin cells from mouse adrenal slices.

Many neurosecretory preparations display two components of depolarization-induced exocytosis: a phasic component synchronized with Ca2+ channel opening, followed by a slower sustained component. We evaluated possible mechanisms underlying this biphasic behavior by stimulating mouse chromaffin cells in situ with both depolarizations and flash photolysis of caged Ca2+. From a direct comparison of the secretory responses to both stimuli, we conclude that phasic and sustained release components originate from a readily releasable pool (RRP) of equally fusion-competent vesicles, suggesting that differences in the vesicles' proximity to Ca2+ channels underlie the biphasic secretory behavior. An intermediate pool in dynamic equilibrium with the RRP ensures rapid recruitment of release-ready vesicles after RRP depletion. Our results are discussed in terms of a refined model for secretion in chromaffin cells.

Adrenal Glands↗