Hanns U. Zeilhofer

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Zeilhofer

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Hanns U.

ORCID

0000-0001-6954-4629

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03742 - Zeilhofer, Hanns U. / Zeilhofer, Hanns U.

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Publications1 - 10 of 34

Spinal prostaglandin E receptors of the EP2 subtype and the glycine receptor α3 subunit, which mediate central inflammatory hyperalgesia, do not contribute to pain after peripheral nerve injury or formalin injection
Hösl, Katharina; Reinold, Heiko; Harvey, Robert J.; et al. (2006)
Pain
Inflammation, peripheral nerve injury and chemical irritants can cause central sensitization in pain pathways. Prostaglandins produced in the CNS induce central sensitization during inflammation mainly by relieving nociceptive neurons from glycinergic inhibition. We have recently identified spinal prostaglandin E receptors of the EP2 subtype (EP2 receptors) and the glycine receptor α3 subunit (GlyRα3) as signal transduction elements involved in the generation of central inflammatory hyperalgesia. It is however still unknown to what extent inhibition of glycine receptors by PGE2 contributes to neuropathic or chemically induced pain. To address this question, we have analyzed mice deficient in the EP2 receptor (EP2−/− mice) or in the GlyRα3 subunit (GlyRα3−/− mice) using the chronic constriction injury (CCI) model of neuropathic pain and the formalin test. We found that EP2−/− mice and GlyRα3−/− mice develop thermal and mechanical hyperalgesia in the CCI model indistinguishable from that seen in wild-type mice. In the formalin test, EP2−/− mice, but not GlyRα3−/− mice, exhibited reduced nocifensive behavior. The lack of a phenotype in GlyRα3−/− mice together with the absence of a facilitating effect of intrathecal PGE2 on formalin-induced nociception in wild-type mice suggests that peripheral rather than spinal EP2 receptors are involved. These results indicate that inhibition of glycinergic neurotransmission by EP2 receptor activation does not contribute to pain following peripheral nerve injury or chemical irritation with formalin. Our results thus provide further evidence that inflammatory hyperalgesia and neuropathic pain involve different mechanisms of central sensitization.
Neuron-specific spinal cord translatomes reveal a neuropeptide code for mouse dorsal horn excitatory neurons
Das Gupta, Rebecca R.; Scheurer, Louis; Pelczar, Pawel; et al. (2021)
Scientific Reports
The spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, a systematic unbiased approach to the use of specific neuromodulatory systems is still missing. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (vGluT2+) and inhibitory GABA and/or glycinergic (vGAT+ or Gad67+) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are not only set apart, as expected, by the expression of genes related to the production, release or re-uptake of their principal neurotransmitters and by genes encoding for transcription factors, but also by a differential engagement of neuromodulator, especially neuropeptide, signaling pathways. Subsequent multiplex in situ hybridization revealed eleven neuropeptide genes that are strongly enriched in excitatory dorsal horn neurons and display largely non-overlapping expression patterns closely adhering to the laminar and presumably also functional organization of the spinal cord grey matter.
Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice
Araya, Anibal; Gallegos, Scarlet; Viveros, Rodrigo; et al. (2021)
British Journal of Pharmacology
Background and Purpose Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10–100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. Experimental Approach We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. Key Results Similar levels of α and β receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αβ receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. Conclusion and Implications Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.
Morphological and neurochemical characterization of glycinergic neurons in laminae I-IV of the mouse spinal dorsal horn
Miranda, Camila O.; Hegedus, Krisztina; Wildner, Hendrik; et al. (2022)
The Journal of Comparative Neurology
A growing body of experimental evidence shows that glycinergic inhibition plays vital roles in spinal pain processing. In spite of this, however, our knowledge about the morphology, neurochemical characteristics, and synaptic relations of glycinergic neurons in the spinal dorsal horn is very limited. The lack of this knowledge makes our understanding about the specific contribution of glycinergic neurons to spinal pain processing quite vague. Here we investigated the morphology and neurochemical characteristics of glycinergic neurons in laminae I-IV of the spinal dorsal horn using a GlyT2::CreERT2-tdTomato transgenic mouse line. Confirming previous reports, we show that glycinergic neurons are sparsely distributed in laminae I-II, but their densities are much higher in lamina III and especially in lamina IV. First in the literature, we provide experimental evidence indicating that in addition to neurons in which glycine colocalizes with GABA, there are glycinergic neurons in laminae I-II that do not express GABA and can thus be referred to as glycine-only neurons. According to the shape and size of cell bodies and dendritic morphology, we divided the tdTomato-labeled glycinergic neurons into three and six morphological groups in laminae I-II and laminae III-IV, respectively. We also demonstrate that most of the glycinergic neurons co-express neuronal nitric oxide synthase, parvalbumin, the receptor tyrosine kinase RET, and the retinoic acid-related orphan nuclear receptor beta (ROR beta), but there might be others that need further neurochemical characterization. The present findings may foster our understanding about the contribution of glycinergic inhibition to spinal pain processing.
In-depth characterization of layer 5 output neurons of the primary somatosensory cortex innervating the mouse dorsal spinal cord.
Frezel, Noémie; Platonova, Evgenia; Voigt, Fabian F.; et al. (2020)
Cerebral Cortex Communications
Neuronal circuits of the spinal dorsal horn integrate sensory information from the periphery with inhibitory and facilitating input from higher central nervous system areas. Most previous work focused on projections descending from the hindbrain. Less is known about inputs descending from the cerebral cortex. Here, we identified cholecystokinin (CCK) positive layer 5 pyramidal neurons of the primary somatosensory cortex (CCK + S1-corticospinal tract [CST] neurons) as a major source of input to the spinal dorsal horn. We combined intersectional genetics and virus-mediated gene transfer to characterize CCK+ S1-CST neurons and to define their presynaptic input and postsynaptic target neurons. We found that S1-CST neurons constitute a heterogeneous population that can be subdivided into distinct molecular subgroups. Rabies-based retrograde tracing revealed monosynaptic input from layer 2/3 pyramidal neurons, from parvalbumin positive cortical interneurons, and from thalamic relay neurons in the ventral posterolateral nucleus. Wheat germ agglutinin-based anterograde tracing identified postsynaptic target neurons in dorsal horn laminae III and IV. About 60% of these neurons were inhibitory and about 60% of all spinal target neurons expressed the transcription factor c-Maf. The heterogeneous nature of both S1-CST neurons and their spinal targets suggest complex roles in the fine-tuning of sensory processing.
Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity
Sugiyama, Kaori; Aida, Tomomi; Nomura, Masatoshi; et al. (2017)
The Journal of Neuroscience
Etifoxine (Stresam®) for chemotherapy-induced pain?
Zeilhofer, Hanns U. (2009)
Pain
Targeting the interaction of GABAB receptors with CaMKII with an interfering peptide restores receptor expression after cerebral ischemia and inhibits progressive neuronal death in mouse brain cells and slices
Balakrishnan, Karthik; Hleihil, Mohammad; Bhat, Musadiq A.; et al. (2023)
Brain Pathology
Cerebral ischemia is the leading cause for long-term disability and mortality in adults due to massive neuronal death. Currently, there is no pharmacological treatment available to limit progressive neuronal death after stroke. A major mechanism causing ischemia-induced neuronal death is the excessive release of glutamate and the associated overexcitation of neurons (excitotoxicity). Normally, GABA(B) receptors control neuronal excitability in the brain via prolonged inhibition. However, excitotoxic conditions rapidly downregulate GABA(B) receptors via a CaMKII-mediated mechanism and thereby diminish adequate inhibition that could counteract neuronal overexcitation and neuronal death. To prevent the deleterious downregulation of GABA(B) receptors, we developed a cell-penetrating synthetic peptide (R1-Pep) that inhibits the interaction of GABA(B) receptors with CaMKII. Administration of this peptide to cultured cortical neurons exposed to excitotoxic conditions restored cell surface expression and function of GABA(B) receptors. R1-Pep did not affect CaMKII expression or activity but prevented its T286 autophosphorylation that renders it autonomously and persistently active. Moreover, R1-Pep counteracted the aberrant downregulation of G protein-coupled inwardly rectifying K+ channels and the upregulation of N-type voltage-gated Ca2+ channels, the main effectors of GABA(B) receptors. The restoration of GABA(B) receptors activated the Akt survival pathway and inhibited excitotoxic neuronal death with a wide time window in cultured neurons. Restoration of GABA(B) receptors and neuroprotective activity of R1-Pep was verified by using brain slices prepared from mice after middle cerebral artery occlusion (MCAO). Treatment with R1-Pep restored normal GABA(B) receptor expression and GABA receptor-mediated K+ channel currents. This reduced MCAO-induced neuronal excitability and inhibited neuronal death. These results support the hypothesis that restoration of GABA(B) receptor expression under excitatory conditions provides neuroprotection and might be the basis for the development of a selective intervention to inhibit progressive neuronal death after ischemic stroke.
GABAergic and glycinergic inhibition in pain pathways
Ganley, Robert; Zeilhofer, Hanns U. (2021)
The Senses: A Comprehensive Reference
GABA and glycine are the fast inhibitory neurotransmitters in the spinal dorsal horn. They inhibit neuronal excitation by opening chloride channels on the somata and dendrites of intrinsic dorsal horn neurons, and on the spinal terminals of peripheral sensory neurons. They are released from interneurons and from neurons descending from higher CNS areas. They limit nociceptive input to the dorsal horn, control the output of dorsal horn projection neurons, and separate non-nociceptive signaling from nociceptive dorsal horn circuits. Peripheral inflammation and nerve injury reduce neuronal inhibition in the dorsal horn through various mechanisms that contribute to hyperalgesia and allodynia. © 2020 Elsevier Inc.
Light-Activated Agonist-Potentiator of GABA_A Receptors for Reversible Neuroinhibition in Wildtype Mice
Maleeva, Galyna; Nin-Hill, Alba; Wirth, Ulrike; et al. (2024)
Journal of the American Chemical Society
Gamma aminobutyric acid type A receptors (GABAARs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABAARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA_AR potentiators, despite their high efficacy, good biodistribution, and favorable molecular properties. One solution to this problem is to use drugs with light-dependent activity (photopharmacology) in combination with on-demand, localized illumination. However, a suitable light-activated potentiator of GABA_ARs has been elusive so far for use in wildtype mammals. We have met this need by developing azocarnil, a diffusible GABAergic agonist-potentiator based on the anxiolytic drug abecarnil that is inactive in the dark and activated by visible violet light. Azocarnil can be rapidly deactivated with green light and by thermal relaxation in the dark. We demonstrate that it selectively inhibits neuronal currents in hippocampal neurons in vitro and in the dorsal horns of the spinal cord of mice, decreasing the mechanical sensitivity as a function of illumination without displaying systemic adverse effects. Azocarnil expands the in vivo photopharmacological toolkit with a novel chemical scaffold and achieves a milestone toward future phototherapeutic applications to safely treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy.

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Hanns U. Zeilhofer

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