Nerve growth factor acutely potentiates synaptic transmission in vitro and induces dendritic growth in vivo on adult neurons in airway parasympathetic ganglia

Abstract

Hazari MS, Pan JH, Myers AC. Nerve growth factor acutely potentiates synaptic transmission in vitro and induces dendritic growth in vivo on adult neurons in airway parasympathetic ganglia. Am J Physiol Lung Cell Mol Physiol 292: L992-L1001, 2007. First published December 28, 2006; doi:10.1152/ajplung.00216.2006.-Elevated levels of nerve growth factor (NGF) and NGF-mediated neural plasticity may have a role in airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Although NGF is known to affect sensory and sympathetic nerves, especially during development, little is known regarding its effect on parasympathetic nerves, especially on adult neurons. The purpose of this study was to analyze the acute and chronic effects of NGF on the electrophysiological and anatomical properties of neurons in airway parasympathetic ganglia from adult guinea pigs. Using single cell recording, direct application of NGF caused a lasting decrease in the cumulative action potential afterhyperpolarization (AHP) and increased the amplitude of vagus nerve-stimulated nicotinic fast excitatory postsynaptic potentials. Neuronal responsiveness to nicotinic receptor stimulation was increased by NGF, which was blocked by the tyrosine kinase inhibitor, K-252a, implicating neurotrophin-specific (Trk) receptors. Neurotrophin-3 and brain-derived neurotrophic factor had no effect on the synaptic potentials, AHP, or nicotinic response; inhibition of cyclooxygenase with indomethacin inhibited the effect of NGF on the cumulative AHP. Forty-eight hours after in vivo application of NGF to the trachealis muscle caused an increase in dendritic length on innervating neurons. These results are the first to demonstrate that NGF increases the excitability of lower airway parasympathetic neurons, primarily through enhanced synaptic efficacy and changes to intrinsic neuron properties. NGF also had dramatic effects on the growth of dendrites in vivo. Such effects may indicate a new role for NGF in the regulation of parasympathetic tone in the diseased or inflamed lower airways.

The Effects of Nerve Growth Factor on Nicotinic Synaptic Transmission in Mouse Airway Parasympathetic Neurons

“…These effects are most likely due to activation of specific receptors for NGF and, based on IF staining, mouse airway cholinergic parasympathetic ganglionic neurons express TrkA receptors, the highaffinity receptor for NGF, not unlike what is observed for all cholinergic neurons in the CNS (23) and peripheral nervous system (11). This is the first study to show that airway parasympathetic neurons express nAChRs containing the a3 and b4 subunits, which may be the primary nAChR subtypes associated with synaptic transmission in this cell type, similar to reports on other autonomic neurons (3).…”

“…The NT, NGF, is increased in asthmatic airways (8) and affects the airway nerve system (9)(10)(11)(12). In mice, levels of NGF have been reported to be increased in infiltrating cells, epithelial cells, and airway smooth muscle after allergic inflammation (13), and is associated with enhanced allergic response (14,15) and airway remodeling (16).…”

“…It has been known for some time that NGF has a rapid neurotransmitter-like action on sensory neurons (e.g., Ref. 17), but determining the acute effects of NTs on autonomic neurons is a relatively understudied area of investigation (11). In this report, we provide evidence that the NGF-selective receptor, TrkA, is expressed by principal parasympathetic ganglionic neurons in mouse lower airways, and that NGF alters electrophysiological and synaptic properties of ganglionic neurons, alterations that may decrease integration (filtering) by these neurons.…”

Neurotransmitters in Airway Parasympathetic Neurons Altered by Neurotrophin-3 and Repeated Allergen Challenge

“…Cytokine-like molecules (neurokines), such as IL-1b, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, glial-derived neurotrophic factors, and others, may also alter nerves directly or indirectly. Although there is sufficient evidence that neurokines and NTs are increased in the blood (7), skin (8), and lungs (4, 9, 10) in inflammatory diseases, there are relatively few studies showing how that these molecules directly affect airway parasympathetic nerves (11)(12)(13).…”

“…For example, chronic allergen exposure enhances cholinergic neurotransmission in sensitized guinea pigs (14), and studies with cultured mouse tracheal segments showed that the cholinergic response can be enhanced by NGF (15) and attenuated by NT-3 (16). NGF also directly affects synaptic responses and neurite growth on principal neurons in adult guinea pig lower airway parasympathetic ganglia (12). In the lower airways, parasympathetic nerve terminals in airway smooth muscle are either cholinergic or nonadrenergic, noncholinergic (NANC), and the balance between these two opposing systems is most likely regulated at the level of the parasympathetic cell body by NTs.…”