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The Journal of Neuroscience, May 15, 2001, 21(10):3375-3382

Nerve Growth Factor Rapidly Induces Prolonged Acetylcholine Release from Cultured Basal Forebrain Neurons: Differentiation between Neuromodulatory and Neurotrophic Influences

Daniel S. Auld^{1, 2}, Françoise Mennicken¹, and Rémi Quirion^{1, 2, 3}

¹ Douglas Hospital Research Center, Montréal, Québec, Canada H4H 1R3, and Departments of ² Neurology and Neurosurgery and ³ Psychiatry, McGill University, Montréal, Québec, Canada H3C 3J7

Long-term exposure to nerve growth factor (NGF) is well established to have neurotrophic effects on basal forebrain cholinergic neurons, but its potential actions as a fast-acting neuromodulator are not as well understood. We report that NGF (0.1-100 ng/ml) rapidly (<60 min) and robustly enhanced constitutive acetylcholine (ACh) release (148-384% of control) from basal forebrain cultures without immediate persistent increases in choline acetyltransferase activity. More ACh was released in response to NGF when exposure was coupled with a higher depolarization level, suggesting activity dependence. In a long-term potentiation-like manner, brief NGF exposure (10 ng/ml; 60 min) induced robust and prolonged increases in ACh release, a capacity that was shared with the other neurotrophins. K252a (10-100 nM), BAPTA-AM (25 µM), and Cd²⁺ (200 µM) prevented NGF enhancement of ACh release, suggesting the involvement of TrkA receptors, Ca²⁺, and voltage-gated Ca²⁺ channels, respectively. Forskolin (10 µM), a cAMP generator, enhanced constitutive ACh release but did not interact synergistically with NGF. Tetrodotoxin (1 µM) and cycloheximide (2 µM) did not prevent NGF-induced ACh release, indicative of action at the level of the cholinergic nerve terminal and that new protein synthesis is not required for this neurotransmitter-like effect, respectively. In contrast, after a 24 hr NGF treatment, distinct protein synthesis-dependent and independent effects on choline acetyltransferase activity and ACh release were observed. These results indicate that neuromodulator/neurotransmitter-like (protein synthesis-independent) and neurotrophic (translation-dependent) actions likely make distinct contributions to the enhancement of cholinergic activity by NGF.

Key words: brain-derived neurotrophic factor; choline acetyltransferase; neurotransmitter release; neuromodulation; cholinergic; neurotrophin

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21103375-08$05.00/0

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