Deletion of muscarinic acetylcholine receptor 3 in microglia impacts brain ischemic injury

Costa, Amanda de Andrade; Haage, Verena; Yang, Seulkee; Wegner, Stephanie; Ersoy, Burcu; Ugursu, Bilge; Rex, André; Kronenberg, Golo; Gertz, Karen; Endres, Matthias; Wolf, Susanne; Kettenmann, Helmut

doi:10.1016/j.bbi.2020.09.008

Cited by 18 publications

(8 citation statements)

References 48 publications

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“…The findings in the current study exclude a cellautonomous effect of heterozygous Nf1 loss on microglia. As such, Nf1 differs from other genes that directly affect microglia function through intrinsic mechanisms, such as Cx3cr1 [52,53], P2ry12 [27,61], Gabbr1 [19], Chrm3 [11], Apoe [28], Tgfbr2 [75], Bmal1 [66], Il6 [57], Il10 [31,70] or Bdnf [47]. It should, however, The number of intersected processes is plotted against their distance from the soma.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Logiacco

Grzegorzek

Cordell

et al. 2023

acta neuropathol commun

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We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.

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Section: Discussionmentioning

confidence: 99%

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Logiacco

Grzegorzek

Cordell

et al. 2023

acta neuropathol commun

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“… 56 Previous studies have demonstrated that the absence of CHRM in microglia affects CI injury. 57 T-type calcium channel enhancer SAK3 inhibits neuronal death after transient CI via CHRM1 stimulation. 58 Previous studies have revealed that ketamine can reduce the need for variable force drug support in patients with septic shock, and its effect may be related to the inhibition of CHRM1.…”

Section: Discussionmentioning

confidence: 99%

Exploration in the Therapeutic and Multi-Target Mechanism of Ketamine on Cerebral Ischemia Based on Network Pharmacology and Molecular Docking

Xiong¹,

Liu²,

Huo³

et al. 2022

IJGM

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Background Ketamine is famous for its dissociative anesthetic properties. It is also analgesic, anti-inflammatory and anti-depressant, and even has a cerebral protective effect. We searched the evidence of the correlation between ketamine target and clinical efficacy and utilized network pharmacology to gather information about the multi-target mechanism of ketamine against cerebral ischemia (CI). We found that ketamine’s clinical significance may be more extensive than previously thought. Methods The drug target of ketamine and CI-related genes were predicted by SwissTargetPrediction, DrugBank, PubChem, GeneCards and DisGeNET databases. The intersection of ketamine’s drug-targets and CI-related genes was analyzed by using GO and KEGG. We predicted the molecular docking between the potential target and ketamine. Results The results indicated that the effect of ketamine on CI was primarily associated with the target of α-synuclein (SNCA), muscarinic acetylcholine receptor M1 (CHRM1) and nitric oxide synthase 1 (NOS1). It principally regulates the signal pathways of circadian transmission, calcium signaling pathway, dopaminergic synapse, cholinergic synapse and glutamatergic synapse. Molecular docking analysis exhibited that hydrogen bond and Pi-Pi interaction were the predominant modes of interaction. Conclusion There are protein targets affected by ketamine in the treatment of CI. Three pivotal targets involving 298 proteins, SNCA, CHRM1 and NOS1, have emerged as multi-target mechanisms for ketamine in CI therapy. Similarly, this study also provides a new idea for introducing network pharmacology into the evaluation of multi-targeted drugs for CI and cerebral protection.

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“… 130 , 131 M4 receptor is abundantly expressed in striatal neurons, which regulates the balance between acetylcholine and dopamine responses. 132 M4 receptor promotes the development of the dopamine hypersensitivity phenotype of schizophrenia. 133 It has been shown that the M5 receptor can potentiate drug addiction by reinforcing rewarded behavior.…”

Section: Gpcrs In Neuropsychiatric Diseasesmentioning

confidence: 99%

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

Wong

et al. 2023

Sig Transduct Target Ther

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Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.

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Deletion of muscarinic acetylcholine receptor 3 in microglia impacts brain ischemic injury

Cited by 18 publications

References 48 publications

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Exploration in the Therapeutic and Multi-Target Mechanism of Ketamine on Cerebral Ischemia Based on Network Pharmacology and Molecular Docking

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

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