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Chronic cholinergic imbalances promote brain diffusion and transport abnormalities
Author(s) -
Meshorer Eran,
Biton Inbal E.,
BenShaul Yoram,
BenAri Shani,
Assaf Yaniv,
Soreq Hermona,
Cohen Yoram
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2957com
Subject(s) - cholinergic , acetylcholinesterase , magnetic resonance imaging , genetically modified mouse , neuroscience , perfusion , blood–brain barrier , medicine , pathology , chemistry , endocrinology , transgene , biology , central nervous system , biochemistry , gene , radiology , enzyme
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 neuro‐deterioration. T 1 ‐ 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 T 1 maps calculated from pre‐ postcontrast T 1 ‐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 immuno‐blot 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. Meshorer, E., Biton, I. E., Ben‐Shaul, Y., Ben‐Ari, S., Assaf, Y., Soreq, H., Cohen, Y. Chronic cholinergic imbalances promote brain diffusion and transport abnormalities. FASEB J. 19, 910–922 (2005)