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

CNS Neurosci Ther. 2020 Mar;26(3):355-366. doi: 10.1111/cns.13223. Epub 2019 Sep 30.


Aims: 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.

Methods: 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.

Results: 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.

Conclusions: Our findings provide a rationale for the development of aminergic wake-promoting therapeutics in hyperammonemic disorders.

Keywords: histamine; hyperammonemia; striatum; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Gene Expression
  • Histamine / pharmacology
  • Histamine / therapeutic use*
  • Histamine Agonists / pharmacology
  • Histamine Agonists / therapeutic use
  • Histamine H3 Antagonists / pharmacology
  • Hyperammonemia / drug therapy*
  • Hyperammonemia / genetics
  • Hyperammonemia / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Organ Culture Techniques


  • Histamine Agonists
  • Histamine H3 Antagonists
  • Histamine

Associated data

  • GENBANK/NM_011982
  • GENBANK/NM_017010059
  • GENBANK/NM_007913
  • GENBANK/NM_001964
  • GENBANK/NM_010118
  • GENBANK/NM_001321037
  • GENBANK/NM_001276684
  • GENBANK/NM_015193
  • GENBANK/NM_007393
  • GENBANK/NM_001101
  • GENBANK/NM_008302
  • GENBANK/NM_001289726
  • GENBANK/NM_009438