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Volume 17, Number 20, Issue of October 15, 1997 pp. 7594-7605
Copyright ©1997 Society for Neuroscience

Absence of p75^NTR Causes Increased Basal Forebrain Cholinergic Neuron Size, Choline Acetyltransferase Activity, and Target Innervation

Received March 20, 1997; revised July 24, 1997; accepted July 28, 1997.

Tracy T. Yeo¹, Jane Chua-Couzens², Larry L. Butcher³, Dale E. Bredesen⁴, Jonathan D. Cooper², Janice S. Valletta², William C. Mobley², and Frank M. Longo¹

¹ Department of Neurology, University of California at San Francisco/Veterans Affairs Medical Center, San Francisco, California 94121, ² Departments of Neurology, Pediatrics, and the Neuroscience Program, University of California at San Francisco, San Francisco, California 94143, ³ Department of Psychology, University of California, Los Angeles, California 90095, and ⁴ Program on Aging, The Burnham Institute, La Jolla, California 92037

Emerging evidence suggests that the p75 neurotrophin receptor (p75^NTR) mediates cell death; however, it is not known whether p75^NTR negatively regulates other neuronal phenotypes. We found that mice null for p75^NTR displayed highly significant increases in the size of basal forebrain cholinergic neurons, including those that are TrkA-positive. Cholinergic hippocampal target innervation also was increased significantly. Activity of the cholinergic neurotransmitter synthetic enzyme choline acetyltransferase (ChAT) was increased in both the medial septum and hippocampus. Upregulation of these cholinergic features was not associated with increased basal forebrain or hippocampal target NGF levels. In contrast, striatal cholinergic neurons, which do not express p75^NTR, showed no difference in neuronal number, size, or ChAT activity between wild-type and p75^NTR null mutant mice. These findings indicate that p75^NTR negatively regulates cholinergic neuronal phenotype of the basal forebrain cholinergic neurons, including cell size, target innervation, and neurotransmitter synthesis.

Key words: p75^NTR; NGF; ChAT; TrkA; transgenic mice; basal forebrain; cholinergic neurons; hippocampus

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