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Interferon-gamma (IFNγ) causes dendrite retraction and synapse loss in rat sympathetic neurons in vivo
Abstracts / Autonomic Neuroscience: Basic and Clinical 177 (2013) 1–65
and Cell Biology, Justus-Liebig-University, Giessen, Germany), P. Hartmann (Institute of Anatomy and Cell Biology, Justus-LiebigUniversity, Giessen, Germany), B.J. Canning (Johns Hopkins University, Asthma and Allergy Center, Baltimore, USA), W. Kummer (Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany) Homeostatic regulation of the balanced chemical composition of the mucosal lining fluid requires appropriate monitoring. Very recently, we have identified a novel epithelium-mediated mechanism for detection of potentially harmful substances that operates in addition to pattern recognition receptors and TLRs. Specialized airway epithelial cells, called brush cells, were identified to be cholinergic. They utilize molecular components of the canonical bitter (dangerous substances, bacterial products) taste transduction cascade as known from the tongue taste buds such as the G-protein -gustducin, phospholipase C beta 2 (PLC 2), transient receptor potential cation channel subfamily M member 5 (TRPM5), and the G-protein coupled taste receptors Tas1R and Tas2R families. In the mouse trachea, both mTas2R105 and mTas2R108, for cycloheximide and denatonium, respectively, were detected in the cholinergic cell population. Denatonium, cycloheximide and 3-oxo-C12homoserine-lacton, a Pseudomonas aeruginosa quorum-sensing molecule, lead to increase in intracellular calcium concentration with subsequent release of acetylcholine and initiation of generalized avoidance reflexes through the excitation of cholinoreceptive sensory nerve fibers in the vicinity of chemosensory cells. Application of bitter substances to the tracheal mucosa of spontaneously breathing mice decreases respiration rate (RR) in an epithelium-dependent manner which is sensitive to mecamylamine, a general nicotinic antagonist. In addition, denatonium also directly activates vagal sensory nerve fibers resulting in short pauses in breathing (“respiratory events”) that are augmented by mecamylamine. Moreover, denatonium has also direct local effects such as decreasing particle transport speed at the mucosal surface. In conclusion, bitter chemosensation acts at multiple sites to detect bacterial colonization or presence of other harmful components in the mucosal lining fluid in the murine trachea. Funded by DFG (KR 4338/1-1) and DZL (Deutsches Zentrum für Lungenforschung). doi:10.1016/j.autneu.2013.05.029
Abstract 5.1 Extra-cardiac neural remodeling in humans with cardiomyopathy and arrhythmias O.A. Ajijolaa, J.J. Wiscoa, H.W. Lambertb, E.M. Starka, A. Mahajana, M.C. FIshbeina, K. Shivkumara (aUniversity of California, Los Angeles, CA, USA), (bWest Virginia University, Morgantown, WV, USA) Background: Intra-myocardial nerve sprouting after myocardial infarction is associated with ventricular arrhythmias (VAs). Whether human stellate ganglia remodel in association with cardiac pathology was unknown. The purpose of our study was to determine whether cardiac pathology is associated with remodeling of the stellate ganglia in humans.
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density and sprouting were also quantified in obtained cadaveric hearts. Mean neuronal size in NL, SCAR, and NICM groups were; 320 ± 4 μm2, 372 ± 10 μm2, and 435 ± 10 μm2 (p = 0.002). No significant differences in neuronal density and fibrosis were present between the groups. Synaptic density in SCAR and NICM ganglia were 57.8 ± 11.2um2/mm2 (p = 0.039) and 44.5 ± 7.9um2/mm2 (p = 0.084) respectively, compared to the NL, 17.8 ± 7um2/mm2 (overall p = 0.162). There were no significant differences in LSG nerve sprouting or myocardial nerve density between the groups. In a porcine model of chronic infarcts, neurochemical changes were also observed in addition to increased neuronal size. Conclusions: Neuronal hypertrophy within LSG is associated with chronic cardiomyopathy in humans. Ganglionic and myocardial nerve sprouting and nerve density were not significantly different. A porcine model recapitulates these findings, and demonstrates neurochemical rmodeling. These changes may be related to increased cardiac sympathetic signaling and VAs. Further studies are needed to determine the electrophysiologic consequences of extra-cardiac neuronal remodeling in humans.
doi:10.1016/j.autneu.2013.05.030
Abstract 5.4 Interferon-gamma (IFNγ) causes dendrite retraction and synapse loss in rat sympathetic neurons in vivo P.J. Lein (University of California-Davis, United States) Inflammation is implicated in the pathogenesis of cardiovascular disease. However, whether and how inflammation contributes to autonomic dysfunction remain poorly characterized. We previously demonstrated that IFNγ causes retraction of dendritic processes in cultures of sympathetic neurons dissociated from rat superior cervical ganglia. Based on these observations, we hypothesized that IFNγ similarly disrupts connectivity of postganglionic sympathetic neurons in vivo. To test this hypothesis, young adult male Sprague Dawley rats were administered purified recombinant rat IFNγ to at levels reported during acute or chronic neuroinflammatory states. Relative to vehicle controls, dendritic arborization and synapse density were significantly reduced in sympathetic neurons of SCG from IFNγ-treated animals. IFNγ-induced loss of receptive surface in the SCG occurred in the absence of reduced neuronal cell viability or decreased trophic interactions between SCG neurons and target tissues. Decreased dendritic complexity and synapse loss was coincident with impaired ganglionic neurotransmission as evidenced by an attenuated baroreflex in animals treated with IFNγ. Based on these observations we propose a novel pathogenic mechanism of neuroinflammatory cardiovascular disease in which IFNγ disrupts neuronal connectivity via selective retraction of dendrites of autonomic neurons, leading to decreased sympathetic excitability. doi:10.1016/j.autneu.2013.05.031
Abstract 6.1 Methods and Results: Left stellate ganglia (LSG) were collected from patients undergoing sympathetic denervation for intractable ventricular arrhythmias, and from cadavers, along with intact hearts. Clinical data on patients and cadaveric subjects were reviewed extensively. We classified ganglia from normal; scarred; and non-ischemic cardiomyopathic hearts without scar as NL (n = 3); SCAR (n = 24); and NICM (n = 7), respectively. Within LSG, we measured neuronal size, density, fibrosis, synaptic density and nerve sprouting. Nerve
Alk signaling in sympathetic neurogenesis and neuroblastoma predisposition H. Rohrer (Research Group Developmental Neurobiology; Max Planck Institute for Brain Research, Deutschordenstr. 46, 60528, Frankfurt/M, Germany), T. Reiff (Research Group Developmental Neurobiology; Max Planck Institute for Brain Research, Deutschordenstr. 46, 60528,
and Cell Biology, Justus-Liebig-University, Giessen, Germany), P. Hartmann (Institute of Anatomy and Cell Biology, Justus-LiebigUniversity, Giessen, Germany), B.J. Canning (Johns Hopkins University, Asthma and Allergy Center, Baltimore, USA), W. Kummer (Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany) Homeostatic regulation of the balanced chemical composition of the mucosal lining fluid requires appropriate monitoring. Very recently, we have identified a novel epithelium-mediated mechanism for detection of potentially harmful substances that operates in addition to pattern recognition receptors and TLRs. Specialized airway epithelial cells, called brush cells, were identified to be cholinergic. They utilize molecular components of the canonical bitter (dangerous substances, bacterial products) taste transduction cascade as known from the tongue taste buds such as the G-protein -gustducin, phospholipase C beta 2 (PLC 2), transient receptor potential cation channel subfamily M member 5 (TRPM5), and the G-protein coupled taste receptors Tas1R and Tas2R families. In the mouse trachea, both mTas2R105 and mTas2R108, for cycloheximide and denatonium, respectively, were detected in the cholinergic cell population. Denatonium, cycloheximide and 3-oxo-C12homoserine-lacton, a Pseudomonas aeruginosa quorum-sensing molecule, lead to increase in intracellular calcium concentration with subsequent release of acetylcholine and initiation of generalized avoidance reflexes through the excitation of cholinoreceptive sensory nerve fibers in the vicinity of chemosensory cells. Application of bitter substances to the tracheal mucosa of spontaneously breathing mice decreases respiration rate (RR) in an epithelium-dependent manner which is sensitive to mecamylamine, a general nicotinic antagonist. In addition, denatonium also directly activates vagal sensory nerve fibers resulting in short pauses in breathing (“respiratory events”) that are augmented by mecamylamine. Moreover, denatonium has also direct local effects such as decreasing particle transport speed at the mucosal surface. In conclusion, bitter chemosensation acts at multiple sites to detect bacterial colonization or presence of other harmful components in the mucosal lining fluid in the murine trachea. Funded by DFG (KR 4338/1-1) and DZL (Deutsches Zentrum für Lungenforschung). doi:10.1016/j.autneu.2013.05.029
Abstract 5.1 Extra-cardiac neural remodeling in humans with cardiomyopathy and arrhythmias O.A. Ajijolaa, J.J. Wiscoa, H.W. Lambertb, E.M. Starka, A. Mahajana, M.C. FIshbeina, K. Shivkumara (aUniversity of California, Los Angeles, CA, USA), (bWest Virginia University, Morgantown, WV, USA) Background: Intra-myocardial nerve sprouting after myocardial infarction is associated with ventricular arrhythmias (VAs). Whether human stellate ganglia remodel in association with cardiac pathology was unknown. The purpose of our study was to determine whether cardiac pathology is associated with remodeling of the stellate ganglia in humans.
25
density and sprouting were also quantified in obtained cadaveric hearts. Mean neuronal size in NL, SCAR, and NICM groups were; 320 ± 4 μm2, 372 ± 10 μm2, and 435 ± 10 μm2 (p = 0.002). No significant differences in neuronal density and fibrosis were present between the groups. Synaptic density in SCAR and NICM ganglia were 57.8 ± 11.2um2/mm2 (p = 0.039) and 44.5 ± 7.9um2/mm2 (p = 0.084) respectively, compared to the NL, 17.8 ± 7um2/mm2 (overall p = 0.162). There were no significant differences in LSG nerve sprouting or myocardial nerve density between the groups. In a porcine model of chronic infarcts, neurochemical changes were also observed in addition to increased neuronal size. Conclusions: Neuronal hypertrophy within LSG is associated with chronic cardiomyopathy in humans. Ganglionic and myocardial nerve sprouting and nerve density were not significantly different. A porcine model recapitulates these findings, and demonstrates neurochemical rmodeling. These changes may be related to increased cardiac sympathetic signaling and VAs. Further studies are needed to determine the electrophysiologic consequences of extra-cardiac neuronal remodeling in humans.
doi:10.1016/j.autneu.2013.05.030
Abstract 5.4 Interferon-gamma (IFNγ) causes dendrite retraction and synapse loss in rat sympathetic neurons in vivo P.J. Lein (University of California-Davis, United States) Inflammation is implicated in the pathogenesis of cardiovascular disease. However, whether and how inflammation contributes to autonomic dysfunction remain poorly characterized. We previously demonstrated that IFNγ causes retraction of dendritic processes in cultures of sympathetic neurons dissociated from rat superior cervical ganglia. Based on these observations, we hypothesized that IFNγ similarly disrupts connectivity of postganglionic sympathetic neurons in vivo. To test this hypothesis, young adult male Sprague Dawley rats were administered purified recombinant rat IFNγ to at levels reported during acute or chronic neuroinflammatory states. Relative to vehicle controls, dendritic arborization and synapse density were significantly reduced in sympathetic neurons of SCG from IFNγ-treated animals. IFNγ-induced loss of receptive surface in the SCG occurred in the absence of reduced neuronal cell viability or decreased trophic interactions between SCG neurons and target tissues. Decreased dendritic complexity and synapse loss was coincident with impaired ganglionic neurotransmission as evidenced by an attenuated baroreflex in animals treated with IFNγ. Based on these observations we propose a novel pathogenic mechanism of neuroinflammatory cardiovascular disease in which IFNγ disrupts neuronal connectivity via selective retraction of dendrites of autonomic neurons, leading to decreased sympathetic excitability. doi:10.1016/j.autneu.2013.05.031
Abstract 6.1 Methods and Results: Left stellate ganglia (LSG) were collected from patients undergoing sympathetic denervation for intractable ventricular arrhythmias, and from cadavers, along with intact hearts. Clinical data on patients and cadaveric subjects were reviewed extensively. We classified ganglia from normal; scarred; and non-ischemic cardiomyopathic hearts without scar as NL (n = 3); SCAR (n = 24); and NICM (n = 7), respectively. Within LSG, we measured neuronal size, density, fibrosis, synaptic density and nerve sprouting. Nerve
Alk signaling in sympathetic neurogenesis and neuroblastoma predisposition H. Rohrer (Research Group Developmental Neurobiology; Max Planck Institute for Brain Research, Deutschordenstr. 46, 60528, Frankfurt/M, Germany), T. Reiff (Research Group Developmental Neurobiology; Max Planck Institute for Brain Research, Deutschordenstr. 46, 60528,