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Histamine-induced plasticity and gene expression in corticostriatal pathway under hyperammonemia.

Authors
  • Sergeeva, Olga A1, 2
  • Chepkova, Aisa N1, 3
  • Görg, Boris3
  • Rodrigues Almeida, Filipe2
  • Bidmon, Hans-Jürgen4
  • Haas, Helmut L1
  • Häussinger, Dieter3
  • 1 Molecular Neurophysiology, Medical Faculty, Institute of Neural and Sensory Physiology, Heinrich-Heine University, Duesseldorf, Germany. , (Germany)
  • 2 Medical Faculty, Institute of Clinical Neurosciences and Medical Psychology, Heinrich-Heine University, Duesseldorf, Germany. , (Germany)
  • 3 Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany. , (Germany)
  • 4 Medical Faculty, C.&O. Vogt Institute for Brain Research, Heinrich-Heine University, Duesseldorf, Germany. , (Germany)
Type
Published Article
Journal
CNS Neuroscience & Therapeutics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Mar 01, 2020
Volume
26
Issue
3
Pages
355–366
Identifiers
DOI: 10.1111/cns.13223
PMID: 31571389
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Histamine H3 receptor (H3R) antagonists/inverse agonists increase vigilance. We studied brain histaminergic pathways under hyperammonemia and the transcriptome of receptors and their signaling cascades to provide a rationale for wake-promoting therapies. We analyzed histamine-induced long-lasting depression of corticostriatal synaptic transmission (LLDhist). As the expression of dopamine 1 receptors (D1R) is upregulated in LGS-KO striatum where D1R-H3R dimers may exist, we investigated actions of H3R and D1R agonists and antagonists. We analyzed transcription of selected genes in cortex and dorsal striatum in a mouse model of inborn hyperammonemia (liver-specific glutamine synthetase knockout: LGS-KO) and compared it with human hepatic encephalopathy. LGS-KO mice showed significant reduction of the direct depression (DD) but not the long-lasting depression (LLD) by histamine. Neither pharmacological activation nor inhibition of D1R significantly affected DDhist and LLDhist in WT striatum, while in LGS-KO mice D1R activation suppressed LLDhist. Histaminergic signaling was found unchanged at the transcriptional level except for the H2R. A study of cAMP-regulated genes indicated a significant reduction in the molecular signature of wakefulness in the diseased cortex. Our findings provide a rationale for the development of aminergic wake-promoting therapeutics in hyperammonemic disorders. © 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

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