Chronic cholinergic imbalances promote brain diffusion and transport abnormalities

Eran Meshorer, Inbal E. Biton, Yoram Ben-Shaul, Shani Ben-Ari, Yaniv Assaf, Hermona Soreq*, Yoram Cohen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Cholinergic imbalances occur after traumatic effects and in the initial stages of neurodegenerative diseases, but their long-lasting effects remained largely unexplained. To address this, we used TgS transgenic mice constitutively overexpressing synaptic acetylcholinesterase (AChE-S) and presenting a complex phenotype of progressive neurodeterioration. T1- and T 2-weighted magnetic resonance (MR) brain images appeared similar. However, diffusion-weighted MRI showed decreased baseline water apparent diffusion coefficient in the brains of TgS animals. Furthermore, contrast-enhanced MRI after gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA) injection demonstrated slower recovery of normal signals in the TgS brains than with controls. Perfusion MR imaging and difference T1 maps calculated from pre- postcontrast T1-weighted MR images indicated accumulation of more Gd-DTPA molecules in the TgS brains than in the parent strain, reflecting impaired blood-brain barrier (BBB) functioning in these transgenic mice. To explore the molecular mechanism(s) underlying these global phenotypes, we performed microarray analysis in the stress-controlling prefrontal cortex of TgS vs. strain-matched wild-type animals. Profound overexpression of numerous ion channels, transporters, and adhesion genes was confirmed by real time RT-PCR tests. Immunohistochemical and immunoblot analyses revealed corresponding increases in the level and cellular distributions of the chloride channel CLCN3 and the water channel AQP4, both of which contribute to BBB maintenance. Our study attributes to balanced cholinergic neurotransmission, a central role in the brain's maintenance of water diffusion and ion transport, and indicates that chronic impairments in this maintenance facilitate neurodeterioration through interference with BBB function.

Original languageAmerican English
Pages (from-to)910-922
Number of pages13
JournalFASEB Journal
Volume19
Issue number8
DOIs
StatePublished - Jun 2005

Keywords

  • Acetylcholinesterase
  • Aquaporin 4
  • Blood-brain barrier
  • Cholinergic neurotransmission

Fingerprint

Dive into the research topics of 'Chronic cholinergic imbalances promote brain diffusion and transport abnormalities'. Together they form a unique fingerprint.

Cite this