The Ventral Medulla & the Sudden Infant Death Syndrome (Serotonin and GABA Neuron Subtypes – their Development and Function)

Based on observations from brainstem tissue of SIDS cases, we hypothesize, as a program, that an importantsubset of SIDS result from medullary defects in serotonin (5-HT)-producing neurons and relatedneurotransmitter systems such as GABA. Evidence suggests that these defects arise during gestation andaffect specific subtypes of, as opposed to all, 5-HT neurons. From this, we reason that SIDS is an embryonicdevelopmental disorder affecting specific subtypes of 5-HT and/or GABA neurons of the medulla. Towardsunderstanding the differential basis for SIDS, we propose experiments designed to decode the developmentaland molecular origins of different neuron subtypes within the medullary 5-HT and GABA neural systems in themouse, and determine the specific properties of these subtypes as relates to homeostatic control. Theseexperiments are made possible via recent, powerful advances: 1) a developmental map of the maturebrainstem 5-HT system that, for the first time, resolves the system into molecularly separable, and thereforegenetically accessible, 5-HT neuron subtypes; 2) the identification of embryonic genetic programs that areinstructive for different GABAergic fates and which are likely employed in the developing medulla; and 3) toolswith sufficient specificity to perturb the activity of (for example, "silence") select 5-HT or GABA subtypes in theliving mouse. Using these tools, we will plot cellular functions and electrophysiological properties onto thedevelopmental maps of medullary 5-HT and GABA neuron subtypes (Aims 1 and 3, respectively). Because ourgoal is to identify neuron subtypes most relevant pathophysiologically to SIDS, we will focus on 5-HT andGABA neuron subtypes of the medulla and their properties as relates to sensing acidosis and/or hypoxia (incollaboration with Project 4) and their functions as relates to control of breathing, heart rate, blood pressureand reflex apnea (in collaboration with Project 2). These are functions which, if impaired, might plausiblycontribute to sudden death. Further, we propose investigating a possible mechanism for regulating 5-HTneuron production, our goal being to decipher the basis for the increased number of 5-HT neurons in SIDScases. The ability to redefine medullary 5-HT and GABA neuron subtypes and their production based on aconstellation of criteria - molecular, developmental, electrophysiological, and functional- is a major strength andinnovation of this proposal and program.