Breathing serves an indispensable biological function and determines essential physiological parameters such as pH and partial pressure of carbon dioxide (PCO2). Central chemosensory neurons detect changes in brain pH as a proxy for changes in PCO2 and cause compensatory changes in respiration to maintain homeostasis of these parameters. Dysfunction of these neurons results in severe morbidity and is implicated in disorders such as congenital central hypoventilation syndrome and sudden infant death syndrome. Yet, the exact molecular mechanisms underlying chemosensitivity have remained largely elusive. In particular, the identity of ion channels that mediate central chemoreception is currently unknown. My preliminary results suggest that the acid-sensing ion channel (ASIC) acts as a chemoreceptor in a subset of neurons located in the nucleus tractus solitarus (NTS), a brainstem region known to be chemosensitive in vivo. However, this raises an important concern: how can ASIC channels contribute to central chemoreception if they are widely expressed even in brain areas not implicated in this process. I hypothesize that a unique combination of ASIC channel properties that confer the requisite pH sensitivity and specific anatomical characteristics (such as dendritic orientation, and axonal projections) may allow a subpopulation of NTS neurons to functionally contribute to central chemoreception.
Aim 1 : Which features of ASIC channels confer chemosensitivity onto a subpopulation of NTS neurons? Biophysical, pharmacological, and molecular tools will be used to determine differences between properties of ASIC channels expressed in NTS neurons that respond to pH 7.0 (responders) and those that do not (non-responders). This will help establish how differences in these properties confer chemosensitivity to only a subset of NTS neurons.
Aim 2 : Do chemosensitive NTS neurons display unique anatomical properties befitting their function? These experiments will combine electrophysiology with anatomical and imaging tools to uncover the anatomical properties of NTS neurons that are chemosensitive in-vitro. Mere expression of pH sensitive channels cannot contribute to central chemoreception. Therefore, whether chemosensitive neurons have unique dendritic properties that would allow them to sample brain pH and the correct axonal projection pattern to provide synaptic drive to respiratory rhythm generating neurons will be determined.

Public Health Relevance

Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) are respiratory disorders characterized by a lack of breathing automaticity and dysfunction of central chemoreception has been proposed to be one of their main causes. Yet, the exact cellular and molecular mechanisms underlying detection of changes in brain PCO2/pH by chemosensitive neurons are not entirely known. Understanding the ion channels involved in central chemoreception will allow us to evaluate if disruption of these channels is involved in the pathophysiology of CCHS and may provide novel targets for pharmacological or gene therapy interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03B-G (20))
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Silberberg, Shai D
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Northwestern University at Chicago
Schools of Medicine
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VanLeeuwen, Jon-Eric; Rafalovich, Igor; Sellers, Katherine et al. (2014) Coordinated nuclear and synaptic shuttling of afadin promotes spine plasticity and histone modifications. J Biol Chem 289:10831-42
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Huda, Rafiq; Pollema-Mays, Sarah L; Chang, Zheng et al. (2012) Acid-sensing ion channels contribute to chemosensitivity of breathing-related neurons of the nucleus of the solitary tract. J Physiol 590:4761-75