Author ORCID Identifier

0000-0002-9790-2857

Date of Award

12-13-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Chun Jiang

Second Advisor

Deborah Baro

Third Advisor

Hang Shi

Abstract

Breathing is generated and controlled by brainstem neurons with several sensory feedback loops, where neurotransmission and neuronal membrane excitability play critical roles. Although such a neural control provides stable and dynamic breathing activity, central respiration depression (CRD) can occur in several diseases and drug misuses, which often leads to severe consequences and death. Questions remain open regarding how the neurotransmission and cellular excitability are changed in CRD; what cellular and molecular mechanisms underlie the changes; and whether they can be corrected with pharmacological agents. This dissertation is to address these questions, with two murine models showing characteristic CRD. One is the mouse model of Rett syndrome (RTT), and the other is the rat model of morphine-induced CRD. Experiments were performed in the models where evidence was obtained with in vivo plethysmography and in vitro recording from brainstem neurons. In the RTT model, we studied the levels of GABAergic and glycinergic signals of neurons in the hypoglossal nucleus (XII) and the dorsal motor nucleus of vagus (DMNV). In the control mice, equal proportions of GABAAergic and glycinergic synaptic inhibitions was found in the XII/ DMNV neurons. In the RTT model, the deficiency in GABAAergic neurotransmission was more severe, and these cells relied more on glycinergic synaptic inhibition. In the morphine-induced CRD model, a decrease in cellular excitability was observed in the locus coeruleus (LC) neurons in which the G-protein coupled inwardly rectifying K+ (GIRK) channels played a role. The GIRK channel is a downstream target of μ opioid receptor (MOR). The activation of MOR by morphine opens the GIRK channels to hyperpolarize LC neurons. Thus, GIRK channel blocker cloperastine (CPS), an antitussive, was tested. We found that CPS alleviated the morphine-induced CRD, and improved morphine-induced inhibition of LC neurons. We also showed that the CPS action involved inhibitions of GIRK channels in LC neurons, presynaptic glutamatergic neurons, and metabotropic glutamate receptors in the presynaptic terminals. Therefore, several molecular targets regulating neurotransmission and membrane excitability have been demonstrated to be critical for CRD. Pharmacologic targeting on the molecules appears to a novel and promising approach to CRD.

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