The respiratory system is highly pliable in its adaptation to low-oxygen (hypoxic) environments. After chronic intermittent hypoxia (CIH), alterations in the regulation of cardiorespiratory system become persistent because of changes in the peripheral chemoreceptor reflex. We present evidence for the induction of a novel form of homeostatic plasticity in this reflex pathway in the nucleus tractus solitarius (NTS), the site of termination of the chemosensory afferent fibers. CIH induces an increase in NTS postsynaptic cell activity initiated by spontaneous presynaptic transmitter release that is counterbalanced by a reduction in evoked synaptic transmission between sensory afferents and NTS second-order cells. This is accomplished via presynaptic mechanisms involving changes in neurotransmitter release and calcium/calmodulin-dependent kinase II activation.

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Mutations in the potassium channel gene Kv1.1 are associated with human episodic ataxia type 1 (EA-1) syndrome characterized by movement disorders and epilepsy. Ataxic episodes in EA-1 patients are often associated with exercise or emotional stress, which suggests a prominent role for the autonomic nervous system. Many of these alterations are reproduced in the Kv1.1-null mouse. Kv1.1 also regulates excitability of sensory neurons essential in cardiovascular and respiratory reflexes. We examined the neural control of the respiratory system of littermate wild-type (control) and Kv1.1-null mice during low O 2 (hypoxia). Immunohistochemical studies demonstrated Kv1.1 in the afferent limb of the carotid body chemoreflex (the major regulator in the response to hypoxia), consisting of the carotid body, petrosal ganglion, and nucleus of the solitary tract (NTS). Respiration was examined by plethysmography. Null mice exhibited a greater increase in respiration during hypoxia compared with controls. In vitro carotid body sensory discharge during hypoxia was greater in null than control mice. In the caudal NTS, evoked EPSCs in brainstem slices were similar between control and null mice. However, the frequency of spontaneous and miniature EPSCs was greater in null mice. Null mice also exhibited more asynchronous release after a stimulus train. These results demonstrate the important role of Kv1.1 in afferent chemosensory activity and suggest that mutations in the human Kv1.1 gene have functional consequences during stress responses that involve respiratory reflexes.

The chemosensory glomus cells of the carotid body (CB) detect changes in O2-tension. Carotid sinus nerve fibers, which originate from peripheral sensory neurons located within the petrosal ganglion, innervate the CB. Release of transmitter from glomus cells activates the sensory afferent fibers to transmit information to the nucleus of the solitary tract in the brainstem. The ion channels expressed within the sensory nerve terminals play an essential role in the ability of the terminal to initiate action potentials in response to transmitter-evoked depolarization. However, with a few exceptions, the identity of ion channels expressed in these peripheral nerve fibers is unknown. This study addresses the expression of voltage-gated channels in the sensory fibers with a focus on channels that set the resting membrane potential and regulate discharge patterns. Using immunohistochemistry and fluorescence confocal microscopy, potassium channel subunits and HCN (hyperpolarization-activated) family members were localized both in petrosal neurons that expressed tyrosine hydroxylase, and the CSN axons within the carotid body. Channels contributing to resting membrane potential including HCN2, responsible in part for Ih current, and the KCNQ2 and KCNQ5 subunits thought to underlie the neuronal “M current” were identified in the sensory neurons and their axons innervating the carotid body. In addition, the results presented here demonstrate expression of several potassium channels that shape the action potential and the frequency of discharge including Kv1.4, Kv1.5, Kv4.3, KCa (BK). The role of these channels should be considered in interpretation of the fiber discharge in response to perturbation of the carotid body environment.