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Sittl R.,Ludwig Maximilians University of Munich | Carr R.W.,Ludwig Maximilians University of Munich | Schwarz J.R.,Institute for Neural Signal Transduction | Grafe P.,Ludwig Maximilians University of Munich
Journal of the Peripheral Nervous System | Year: 2010

Flupirtine is an activator of Kv7 (KCNQ/M) potassium channels that has found clinical use as an analgesic with muscle relaxant properties. Kv7 potassium channels are expressed in axonal membranes and pharmacological activation of these channels may restore abnormal nerve excitability. We have examined the effect of flupirtine on the electrical excitability of myelinated axons in isolated segments of rat sural nerve. Axonal excitability was studied in vitro with the same parameters used by clinical neurophysiologists to assess peripheral nerve excitability in situ. Application of flupirtine in low micromolar concentrations resulted in an increase in threshold current, a reduction of refractoriness and an increase in post-spike superexcitability. These effects are consistent with an increase in Kv7 conductance and membrane hyperpolarization. Flupirtine also enhanced and prolonged the late, long-lasting period of axonal subexcitability that follows a short burst of action potentials. This effect was blocked by XE 991 (10 μM), an antagonist of Kv7 channels. In summary, flupirtine affects measures of excitability that are altered in the myelinated axons of patients with peripheral nerve disorders. This indicates that neuropathies with abnormal nerve excitability parameters corresponding to those affected by flupirtine may benefit from activation of axonal Kv7 potassium channels. © 2010 Peripheral Nerve Society. Source

Voigt A.,German Institute of Human Nutrition | Voigt A.,Institute for Neural Signal Transduction | Hubner S.,German Institute of Human Nutrition | Lossow K.,German Institute of Human Nutrition | And 4 more authors.
Chemical Senses | Year: 2012

Characterization of the peripheral taste system relies on the identification and visualization of the different taste bud cell types. So far, genetic strategies to label taste receptor cells are limited to sweet, sour, and salty detecting cells. To visualize Tas1r1 umami and Tas2r131 bitter sensing cells, we generated animals in which the Tas1r1 and Tas2r131 open reading frames are replaced by expression cassettes containing the fluorescent proteins mCherry or hrGFP, respectively. These animals enabled us to visualize and quantify the entire oral Tas1r1 and Tas2r131 cell populations. Tas1r1-mCherry cells were predominantly detected in fungiform papillae, whereas Tas2r131-hrGFP cells, which are ~4-fold more abundant, were mainly present in foliate and vallate papillae. In the palate, both cell types were similarly distributed. Mice carrying both recombinant alleles demonstrated completely segregated Tas1r1 and Tas2r131 cell populations. Only ~50% of the entire bitter cell population expressed hrGFP, indicating that bitter taste receptor cells express a subset of the bitter receptor repertoire. In extragustatory tissues, mCherry fluorescence was observed in testis and hrGFP fluorescence in testis, thymus, vomeronasal organ, and respiratory epithelium, suggesting that only few extraoral sites express Tas2r131 and Tas1r1 receptors at levels comparable to taste tissue. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

Kumar D.,Saarland University | Periasamy V.,Saarland University | Freese M.,Institute for Neural Signal Transduction | Voigt A.,Institute for Neural Signal Transduction | Boehm U.,Saarland University
Endocrinology | Year: 2015

The neuropeptide kisspeptin is a major regulator of the hypothalamus-pituitary-gonadal axis. Although it has long been known that kisspeptin and its receptor G protein-coupled receptor 54 (GPR54) are expressed in the developing brain well before puberty onset, the potential role of kisspeptin/GPR54 signaling in the embryonic brain has remained mysterious. Recent studies in female mice have shown that kisspeptin neurons in the arcuate nucleus of the hypothalamus (ARC) already communicate with a subset of GnRH neurons in utero. Whether this specific neural circuit is also formed in the developing male brain is not known. Here, we used a combination of different genetic strategies to analyze the ontogeny and development of the kisspeptin/GPR54 system in the male mouse brain. We demonstrate orchestrated onset of kisspeptin and GPR54 expression in the male embryonic mouse brain and find that androgen receptor and estrogen receptor-α immunoreactivity within the male brain delineate the birthplace of kisspeptin neurons in the ARC. Using conditional transsynaptic tracing from kisspeptin neurons, we find that ARC kisspeptin neurons already communicate with a subset of GnRH neurons in utero and that the neural circuits between ARC kisspeptin and GnRH neurons in the male mouse brain are established before birth. Furthermore, we also show that the connectivity between kisspeptin and GnRH neurons does not depend on the spatial position of GnRH neurons. Our data delineatethe maturing neural circuits underlying control of the reproductive axis in the male embryonic mouse brain. Copyright © 2015 by the Endocrine Society. Source

Kumar D.,Saarland University | Candlish M.,Saarland University | Periasamy V.,Saarland University | Avcu N.,Institute for Neural Signal Transduction | And 2 more authors.
Endocrinology | Year: 2015

The neuropeptide kisspeptin is a potent stimulator of GnRH neurons and has been implicated as a major regulator of the hypothalamus-pituitary-gonadal axis. There are mainly two anatomically segregated populations of neurons that express kisspeptin in the female hypothalamus: one in the anteroventral periventricular nucleus (AVPV) and the other in the arcuate nucleus (ARC). Distinct roles have been proposed for AVPV and ARC kisspeptin neurons during reproductive maturation and in mediating estrogen feedback on the hypothalamus-pituitary-gonadal axis in adults. Despite their pivotal role in the regulation of reproductive physiology, little is known about kisspeptin neuron connectivity. Although previous data suggest heterogeneity within the AVPV and ARC kisspeptin neuron populations, how many and which of these potential kisspeptin neuron subpopulations are actually communicating with GnRH neurons is not known. Here we used a combinatorial genetic transsynaptic tracing strategy to start to analyze the connectivity of individual kisspeptin neurons with the GnRH neuron population in female mice with a single-cell resolution. We find that only subsets of AVPV and ARC kisspeptin neurons are synaptically connected with GnRH neurons.Wedemonstrate that the majority of kisspeptin neurons within the AVPV and ARC does not communicate with GnRH neurons. Furthermore, we show that all kisspeptin neurons within the AVPV connected to GnRH neurons are estrogen sensitive and that most of these express tyrosine hydroxylase. Our data demonstrate functional specialization within the two kisspeptin neuron populations. © 2015 by the Endocrine Society. Source

Voigt A.,German Institute of Human Nutrition | Voigt A.,Institute for Neural Signal Transduction | Bojahr J.,German Institute of Human Nutrition | Narukawa M.,German Institute of Human Nutrition | And 4 more authors.
Journal of Neuroscience | Year: 2015

Taste perception begins in the oral cavity by interactions of taste stimuli with specific receptors. Specific subsets of taste receptor cells (TRCs) are activated upon tastant stimulation and transmit taste signals to afferent nerve fibers and ultimately to the brain. How specific TRCs impinge on the innervating nerves and how the activation of a subset of TRCs leads to the discrimination of tastants of different qualities and intensities is incompletely understood.Toinvestigate the organization of taste circuits,weused gene targeting to express the transsynaptic tracer barley lectin (BL) in the gustatory system of mice. Because TRCs are not synaptically connected with the afferent nerve fibers, we first analyzed tracer production and transfer within the taste buds (TBs). Surprisingly, we found that BL is laterally transferred across all cell types in TBs of mice expressing the tracer under control of the endogenous Tas1r1 and Tas2r131 promotor, respectively. Furthermore, although we detected the BL tracer in both ganglia and brain, we also found local low-level Tas1r1 and Tas2r131 gene, and thus tracer expression in these tissues. Finally, we identified the Tas1r1 and Tas2r131-expressing cells in the peripheral and CNS using a binary genetic approach. Together, our data demonstrate that genetic transsynaptic tracing from bitter and umami receptor cells does not selectively label taste-specific neuronal circuits and reveal local taste receptor gene expression in the gustatory ganglia and the brain. © 2015 the authors. Source

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