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The Journal of Neuroscience, January 15, 2000, 20(2):834-844

Nerve Growth Factor (NGF) Augments Cortical and Hippocampal Cholinergic Functioning after p75NGF Receptor-Mediated Deafferentation But Impairs Inhibitory Avoidance and Induces Fear-Related Behaviors

Jürgen Winkler^{1, 2, 3}, Gilbert A. Ramirez, Leon J. Thal^{1, 2}, and Jerene J. Waite^{1, 2}

¹ Department of Neurosciences, University of California San Diego, La Jolla, California 92093-0624, ² Neurology Service, Veterans Affairs Medical Center San Diego, San Diego, California 92161, and ³ Department of Neurology, University of Regensburg, D-93053 Regensburg, Germany

Nerve growth factor (NGF) enhances cholinergic functioning in animals with a compromised cholinergic basal forebrain (CBF). Immunotoxic lesions targeting low-affinity NGF receptor (p75NGF receptor)-bearing CBF neurons provide a selective model for testing the effects of NGF on residual cholinergic neurons. Rats received PBS or the immunotoxin 192IgG-saporin (192Sap) intracerebroventricularly at two doses (1 or 2.7 µg) known to produce different degrees of cholinergic deficit. Seven weeks after lesioning, half of each group received either NGF or cytochrome c intracerebroventricularly for 7 weeks. The two doses of 192Sap produced 50 and 80% depletions of choline acetyltransferase (ChAT) activity in the neocortex and hippocampus. NGF produced the greatest increase in ChAT activity in controls, intermediate in low-lesioned, and smallest in highly lesioned animals. NGF-treated animals showed reduced weight gain, hyper-responsiveness to acoustic stimuli, and decreased inhibitory avoidance. Although general motor behavior was affected by neither 192Sap nor NGF in an open field task, highly lesioned rats took longer to reach the platform during water maze testing. Impaired spatial orientation in finding a hidden platform at the previously acquired position was mitigated by NGF. Hypertrophic changes of residual CBF neurons, Schwann cell hyperplasia, and aberrant axonal sprouting around the medulla were observed in NGF-treated animals only, independent of the preexisting lesion. Our results indicate that NGF has a limited capacity to enhance functioning of residual CBF neurons. More importantly, NGF augmented fear-related behaviors and adverse neuroproliferative changes that may restrict its therapeutic use.

Key words: basal forebrain; immunotoxin; 192IgG-saporin; NGF; water maze; inhibitory avoidance; startle response; choline acetyltransferase; low-affinity nerve growth factor receptor

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Copyright © 2000 Society for Neuroscience  0270-6474/00/202834-11$05.00/0

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