Cholinergic neurons of mouse intrinsic cardiac ganglia contain noradrenergic enzymes, norepinephrine transporters, and the neurotrophin receptors tropomyosin-related kinase A and p75

Abstract Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the ve...

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Published in:	Neuroscience Vol. 156; no. 1; pp. 129 - 142
Main Authors:	Hoard, J.L, Hoover, D.B, Mabe, A.M, Blakely, R.D, Feng, N, Paolocci, N
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 22-09-2008 Elsevier
Subjects:	Acetylcholine - metabolism Animals Autonomic Pathways - cytology Autonomic Pathways - metabolism Biological and medical sciences cardiac ganglia choline transporter Dopamine beta-Hydroxylase - metabolism Fluorescent Antibody Technique Fundamental and applied biological sciences. Psychology Ganglia, Parasympathetic - cytology Ganglia, Parasympathetic - metabolism heart Heart - innervation Heart - physiology Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Neurology Neurons - cytology Neurons - metabolism Norepinephrine - metabolism Norepinephrine Plasma Membrane Transport Proteins - metabolism parasympathetic Peripheral nervous system. Autonomic nervous system. Neuromuscular transmission. Ganglionic transmission. Electric organ Phenotype Primates Receptor, Nerve Growth Factor - metabolism Receptor, trkA - metabolism Stellate Ganglion - cytology Stellate Ganglion - metabolism sympathetic Synaptic Transmission - physiology Tyrosine 3-Monooxygenase - metabolism Vertebrates: nervous system and sense organs Vesicular Acetylcholine Transport Proteins - metabolism vesicular acetylcholine transporter Vesicular Monoamine Transport Proteins - metabolism norepinephrine ACh neuropeptide Y DBH phosphate-buffered saline CHT BSA VMAT2 small intensely fluorescent cells PBS tropomyosin-related kinase A dopamine β-hydroxylase protein gene product 9.5 IR NGF heart tyrosine hydroxylase norepinephrine transporter NE bovine serum albumin VAChT sympathetic vesicular acetylcholine transporter intrinsic cardiac ganglia PGP 9.5 nerve growth factor NPY ChAT WT knockout KO cardiac ganglia ICG vesicular monoamine transporter type 2 choline acetyltransferase dopamine transporter TrkA parasympathetic TH high affinity choline transporter ICN DAT immunoreactive SIF cells intrinsic cardiac neuron acetylcholine NET wild-type choline transporter Heart Neurotrophin Cholinergic neuron Vesicular acetylcholine transporter Autonomic nervous system Carrier protein Biological receptor Tropomyosin kinase Enzyme Transferases Rodentia Catecholamine Sympathetic nervous system Vertebrata Mammalia Mouse Animal Choline Norepinephrine Circulatory system Parasympathetic nervous system
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Summary:	Abstract Half of the cholinergic neurons of human and primate intrinsic cardiac ganglia (ICG) have a dual cholinergic/noradrenergic phenotype. Likewise, a large subpopulation of cholinergic neurons of the mouse heart expresses enzymes needed for synthesis of norepinephrine (NE), but they lack the vesicular monoamine transporter type 2 (VMAT2) required for catecholamine storage. In the present study, we determined the full scope of noradrenergic properties (i.e. synthetic enzymes and transporters) expressed by cholinergic neurons of mouse ICG, estimated the relative abundance of neurons expressing different elements of the noradrenergic phenotype, and evaluated the colocalization of cholinergic and noradrenergic markers in atrial nerve fibers. Stellate ganglia were used as a positive control for noradrenergic markers. Using fluorescence immunohistochemistry and confocal microscopy, we found that about 30% of cholinergic cell bodies contained tyrosine hydroxylase (TH), including the activated form that is phosphorylated at Ser-40 (pSer40 TH). Dopamine β-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake. Yet, cholinergic somata lacked VMAT2, precluding the potential for NE storage and vesicular release. In contrast to cholinergic somata, cardiac nerve fibers rarely showed colocalization of cholinergic and noradrenergic markers. Instead, these labels were closely apposed but clearly distinct from each other. Since cholinergic somata expressed several noradrenergic proteins, we questioned whether these neurons might also contain trophic factor receptors typical of noradrenergic neurons. Indeed, we found that all cholinergic cell bodies of mouse ICG, like noradrenergic cell bodies of the stellate ganglia, contained both tropomyosin-related kinase A (TrkA) and p75 neurotrophin receptors. Collectively, these findings demonstrate that mouse intrinsic cardiac neurons (ICNs), like those of humans, have a complex neurochemical phenotype that goes beyond the classical view of cardiac parasympathetic neurons. They also suggest that neurotrophins and local NE synthesis might have important effects on neurons of the mouse ICG.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2008.06.063