Developing Neonatal Rat Sympathetic and Sensory Neurons Differ in Their Regulation of 5-HT₃Receptor Expression

Abstract

Serotonin 5-HT 3 receptors (5-HT 3 Rs) are ligand-gated ion channels expressed by many peripheral neurons and are involved in several physiological processes. To learn more about the developmental regulation of 5-HT 3 R expression, we investigated rat sympathetic and vagal sensory neurons. We found that sympathetic and sensory neurons differ in their regulation of 5-HT 3 R expression during early postnatal life and as these neurons develop in culture. In SCG neurons 5-HT 3 R transcript levels are low at postnatal day 1 (P1) and increase 7.5-fold by P21; this increase occurs even after elimination of preganglionic innervation. In comparison, 5-HT 3 R mRNA levels in P1 nodose neurons are over 14-fold greater than in P1 SCG and change little by P21. We show that 5-HT 3 R transcript levels in nodose neurons depend on intact target innervation and drop by 60% after axotomy. When P1 SCG neurons develop in culture, we observed a significant increase in 5-HT 3 R expression: after 7 d in culture, transcript levels increase ninefold versus a threefold increase for neurons developing for 7 d in vivo. In contrast, 5-HT 3 R mRNA levels in cultured nodose neurons drop by 70% within 24 hr; however, this drop is transient. After 2 d, transcript levels begin to increase, and after 7 d, they are above initial values. We show that this delayed increase in 5-HT 3 R expression depends on neurotrophins. In both nodose and sympathetic neurons we found that the changes in 5-HT 3 R gene expression correlate directly with the appearance of 5-HTevoked current densities. Key words: 5-HT 3 receptor; ligand-gated ion channel; sympathetic; superior cervical ganglion; sensory; nodose; trigeminal; mRNA expression; neurotrophins; axotomyThe serotonin 5-HT 3 receptor (5-HT 3 R), a neurotransmittergated ion channel (Yakel and Jackson, 1988;Derkach et al., 1989;Maricq et al., 1991) present on many mammalian peripheral neurons, participates in several diverse physiological functions (Fozard, 1984;Jackson and Yakel, 1995). Activation of 5-HT 3 Rs located on peripheral vagal sensory nerve endings initiates reflexes affecting respiration, circulation, emesis, and swallowing (Douglas, 1975;Sanders-Bush and Mayer, 1996). 5-HT 3 Rs on spinal and vagal sensory neurons are involved in nociceptive signaling and nausea (Fozard, 1984). In the C NS 5-HT 3 Rs are implicated in anxiety, depression, and drug dependence (Apud, 1993;Greenshaw, 1993). In addition, 5-HT 3 Rs are expressed by sympathetic neurons; however, the role for these receptors in sympathetic f unction has not been f ully determined (Wallis and North, 1978;Yang et al., 1992).Many vagal afferent neurons expressing 5-HT 3 Rs are located in the nodose ganglion. These sensory neurons have typical unipolar polarities; their axons bif urcate into a peripheral branch that innervates much of the viscera, including heart, lungs, trachea, and gut, and a central branch that terminates mainly in the nucleus tractus solitarius (Andresen and Kunze, 1994). The physiological responses to serotonin elicited from ...

Therapeutics of 5-HT3 receptor antagonists: Current uses and future directions

“…Distribution of the 5-HT 3A receptor subunit, as measured by mRNA levels and immuncytochemistry, correlates well with radio-ligand binding studies conducted with high affinity competitive antagonists of the 5-HT 3 receptor (Kilpatrick et al, 1987; Barnes et al, 1989; Laporte et al, 1992; Tecott et al, 1993; Morales et al, 1996; Morales and Bloom, 1997; Rosenberg et al, 1997). Expression of 5-HT 3A receptor mRNA has been measured in the rat forebrain, hippocampus, amygdale, spinal tract of the trigeminal nerve, facial nerve, and the spinal cord dorsal horn (Tecott et al, 1993; Morales and Bloom, 1997).…”

Nicotinic Acetylcholine Receptors on Vagal Afferent Neurons

“…However, if these same neurons develop in culture without their ganglionic satellite cells and with NGF, they extend dendrites and develop functional cholinergic nicotinic synapses among one another—characteristics more typical of autonomic neurons than of sensory neurons 7,17. We have also shown that neurotrophins affect the expression of 5‐HT 3 R on nodose neurons 18. From these studies, we conclude that the surrounding ganglionic satellite cells exert an important developmental influence(s) on the developing nodose neurons.…”

“…7,17 We have also shown that neurotrophins affect the expression of 5-HT 3 R on nodose neurons. 18 From these studies, we conclude that the surrounding ganglionic satellite cells exert an important developmental influence(s) on the developing nodose neurons. Moreover, we find that this influence operates over a brief developmental window, lasting about 2 weeks, before the neurons become fully committed to a sensory phenotype: if neonatal nodose neurons develop with satellite cells for about 2 weeks, either in vivo or in culture, removing the satellite cells and adding NGF has little effect on their subsequent differentiation.…”

Chemical Neuroanatomy of 5-HT Receptor Subtypes in the Mammalian Brain

“…Most of these cortical cells are GABAergic (168,169). Neurons of the peripheral ganglia contain 5-HT 3A subunit receptor mRNA (166,167,170). In contrast, 5-HT 3B receptor subunit transcripts are restricted to peripheral neurons (167) and are not detected in neurons of the central nervous system.…”