ORCID Profile
0000-0001-6954-4629
Current Organisations
University of Zurich
,
ETH-Bereich Hochschulen
,
Universitat Zurich
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Publisher: Wiley
Date: 17-09-2021
DOI: 10.1111/BPH.15649
Abstract: 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. 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. 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. 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.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.CELREP.2018.01.004
Abstract: Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2006
DOI: 10.1016/J.PAIN.2006.06.011
Abstract: 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 alpha3 subunit (GlyR alpha3) 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 GlyR alpha3 subunit (GlyR alpha3-/- mice) using the chronic constriction injury (CCI) model of neuropathic pain and the formalin test. We found that EP2-/- mice and GlyR alpha3-/- 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 GlyR alpha3-/- mice, exhibited reduced nocifensive behavior. The lack of a phenotype in GlyR alpha3-/- 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.
Publisher: The Optical Society
Date: 02-10-2015
DOI: 10.1364/BOE.6.004228
Publisher: Springer Science and Business Media LLC
Date: 18-07-2023
DOI: 10.1038/S41598-023-38605-9
Abstract: Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1038/S41593-022-01013-9
Abstract: Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-05-2004
Abstract: Prostaglandin E 2 (PGE 2 ) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR α3) by PGE 2 -induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR α3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR α3 not only lack the inhibition of glycinergic neurotransmission by PGE 2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE 2 injection or peripheral inflammation. Thus, GlyR α3 may provide a previously unrecognized molecular target in pain therapy.
Publisher: Wiley
Date: 20-08-2004
DOI: 10.1002/CNE.20267
Abstract: Gamma-aminobutyric acid (GABA) and glycine are the major inhibitory neurotransmitters in the retina, glycine being produced in approximately half of all amacrine cells. Whereas retinal cell types expressing the glycine receptor (GlyR) alpha1 and alpha3 subunits have been mapped, the role of the alpha2 subunit in retinal circuitry remains unclear. By using immunocytochemistry, we localized the alpha2 subunit in the inner plexiform layer (IPL) in brightly fluorescent puncta, which represent postsynaptically clustered GlyRs. This was shown by doubly labeling sections for GlyR alpha2 and bassoon (a presynaptic marker) or gephyrin (a postsynaptic marker). Synapses containing GlyR alpha2 were rarely found on ganglion cell dendrites but were observed on bipolar cell axon terminals and on amacrine cell processes. Recently, an amacrine cell type has been described that is immunopositive for glycine and for the vesicular glutamate transporter vGluT3. The processes of this cell type were presynaptic to GlyR alpha2 puncta, suggesting that vGluT3 amacrine cells release glycine. Double labeling of sections for GlyR alpha1 and GlyR alpha2 subunits showed that they are clustered at different synapses. In sections doubly labeled for GlyR alpha2 and GlyR alpha3, approximately one-third of the puncta were colocalized. The most abundant GlyR subtype in retina contains alpha3 subunits, followed by those containing GlyR alpha2 and GlyR alpha1 subunits.
No related grants have been discovered for Hanns Ulrich Zeilhofer.