Date of Completion

12-27-2013

Embargo Period

12-27-2013

Keywords

neuroscience, physiology, breathing, chemoreception, purinergic signaling, astrocytes

Major Advisor

Daniel K Mulkey

Associate Advisor

Akiko Nishiyama

Associate Advisor

Anastasios Tzingounis

Field of Study

Physiology and Neurobiology

Open Access

Open Access

Abstract

Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue pH/CO2. It is particularly important during sleep and its disruption has been associated with certain pathologies, including central sleep apnea and central congenital hypoventilation syndrome. A region of the brainstem called the retrotrapezoid nucleus (RTN) is thought to be an important site of central chemoreception. Recent evidence suggests that RTN chemoreception involves two mechanisms. The first appears to be H+-mediated activation of neurons via inhibition of pH-sensitive potassium channels. More recently, a second sensing mechanism has been identified; paracrine release of ATP in the RTN region that acts on P2 receptors. It has been postulated that astrocytes in the region release ATP, as they have been found to release ATP in other brain regions in response to various stimuli. However, the mechanisms by which astrocytes sense CO2 and/or pH are not known. Astrocytes in many brain regions are known to express Kir4.1 and/or Kir4.1-Kir5.1 potassium channels, which are highly pH sensitive. In addition, Kir4.1-Kir5.1 is expressed in the RTN. I hypothesize that RTN astrocyte sense CO2/H+ by inhibition of Kir4.1-Kir5.1 channels, which results in membrane depolarization. I also hypothesize that ATP released via connexin hemichannels in response to CO2/H+ acts on P2-receptors on RTN neurons to increase neuronal action potential firing, and that this purinergic mechanism of chemoreception is restricted to the ventral surface, affecting primarily RTN neurons. The evidence described in this thesis supports four main conclusions; (1) Kir4.1/Kir5.1 channels, and the sodium bicarbonate cotratransporter, are the mechanism of RTN astrocyte chemosensitivity, (2) CO2-driven purinergic signaling in the RTN is required for complete chemosensation in vivo and in vitro, (3) CO2-evoked ATP release is dependent on connexin hemichannels and (4) these purinergic mechanisms are specific to the RTN.

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