A decrease in number and size of basal forebrain cholinergic neurons is paralleled by diminished hippocampal cholinergic innervation in mice lacking LAR protein tyrosine phosphatase activity

Esther M.M. Van Lieshout, I Van der Heijden, W.J.A.J Hendriks, C.E.E.M Van der Zee

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41 Citations (Scopus)

Abstract

The leukocyte common antigen-related (LAR) receptor, composed of an extracellular region with three immunoglobulin-like and eight fibronectin type III-like domains, and a cytoplasmic region containing two protein tyrosine phosphatase domains, is thought to play a role in axonal outgrowth and guidance during neural development. LAR mutant mice were generated completely lacking the two cytoplasmic protein tyrosine phosphatase domains, resulting in the loss of ability to bind intracellular associating proteins, but (may be) still containing the ability to perform extracellular functions. A reduction in size of basal forebrain cholinergic neurons and diminished hippocampal innervation reported for knockout mice that contain a leaky gene trap inserted into the 5′ part of the LAR gene [Yeo T. T. et al. (1997) J. Neurosci. Res. 47, 348–360] warranted a computer-assisted quantitative image analysis throughout the basal forebrain and hippocampus of our LAR mutant mice. The total number, longest diameter and cell body area were calculated for the choline acetyltransferase-positive neurons in the medial septum and vertical diagonal band, and optical density measurements were performed to determine the extent of acetyl cholinesterase-positive fibre innervation of the different layers in the dentate gyrus. In LAR mutant mice, the number of cholinergic cells was significantly reduced (∼25%) in the vertical diagonal band. Also, the cross-sectional area of the cholinergic neurons in the medial septum and vertical diagonal band was reduced (5%). These findings were paralleled by a diminished cholinergic innervation of the supragranular (18%) and molecular (4%) layers of the dentate gyrus.

Thus, LAR protein tyrosine phosphatase activity appears crucial for size, number and target projection of basal forebrain cholinergic neurons, further strengthening a role for LAR in CNS development.
Original languageEnglish
Pages (from-to)833-841
JournalNeuroscience
Volume102
Issue number4
DOIs
Publication statusPublished - 14 Feb 2001
Externally publishedYes

Bibliographical note

Acknowledgements
We would like to thank Jack Fransen and Hans Smits for excellent assistance with the PC image program. T. Yang and F. M. Longo are greatly acknowledged for running western blots and, along with T. T. Yeo, for critically reading the manuscript. Also, employees of the Department of Anatomy of the University of Nijmegen are acknowledged for giving us access to their Vibratome, perfusion pump and mercury column. Colleagues at the Central Animal Facility of the University Medical Centre St. Radboud are acknowledged for their help and advice concerning mouse breeding and housing. Part of this project was supported by grant KUN 98-1810 (W.J.A.J.H.) from the Dutch Cancer Society.

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