Chronic intermittent hypoxia reduces neurokinin-1 (NK1) receptor density in small dendrites of non-catecholaminergic neurons in mouse nucleus tractus solitarius

Abstract

Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK 1 ) receptors. Acute hypoxia results in internalization of NK 1 receptors, suggesting that CIH also may affect the subcellular distribution of NK 1 receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the ratelimiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK 1 receptor and TH in the cNTS of male mice subjected to 10 days or 35 days of CIH or intermittent air. Electron microscopy revealed that NK 1 receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK 1 receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region-specific decrease in the cytoplasmic (10 and 35 days, P< 0.05, unpaired Student t-test) and extrasynaptic plasmalemmal (35 days, P< 0.01, unpaired Student t-test) density of NK 1 immunogold particles exclusively in small (<0.1 µm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration-dependent reduction in the availability of NK 1 receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients.

NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury

“…We identified mature synapses on serial sections and defined them as described previously (31). Details are provided in SI Materials and Methods.…”

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

“…SP and the NK1R have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation [ 14 – 16 ], integration of cardiovascular control [ 17 ], modulation of the baroreceptor reflex [ 18 ] and mediation of the chemoreceptor reflex in response to hypoxia [ 19 , 20 , 28 ]. In this study, we observed abnormalities related to development and sex in NK1R binding within multiple nuclei of the medullary homeostatic network in SIDS cases incuding absolute reductions in binding in the NTS and and all sub-divisions of IO nuclei (PIO, MAO, DAO).…”

“…The NTS houses the primary relay station for brainstem transmission of important respiratory and cardiovascular reflexes and is enriched with a high density of SP containing axon terminals [ 29 , 30 ]. Evidence from animal studies indicates a functional role for SP in the NTS as a central integrator of cardiovascular control [ 17 ], modulator of baroreceptor reflex sensitivity [ 18 ] and a primary excitatory mediator of the chemoreceptor reflex in response to hypoxia [ 19 , 20 ]. In rodent models, activation of NK1R by SP in the NTS stimulates respiration, while loss of NK1R reduces the respiratory response, severely impairing the chemoreceptor reflex and selective lesion of NK1R expressing neurons in the NTS blunts cardiovascular reflexes [ 31 , 32 ].…”

“…The neuropeptide SP has been shown to play an integral role in the modulation of homeostatic function in the medulla, in conjunction with other neurochemicals such as 5-HT, including regulation of respiratory rhythm generation [ 14 – 16 ], integration of cardiovascular control [ 17 ], modulation of the baroreceptor reflex [ 18 ] and mediation of the chemoreceptor reflex in response to hypoxia [ 19 , 20 ]. Abnormalities in SP neurotransmission may play, therefore, a role in homeostatic dysfunction in conjunction with other neurotransmitter network deficits in SIDS.…”

Substance P Differentially Modulates Firing Rate of Solitary Complex (SC) Neurons from Control and Chronic Hypoxia-Adapted Adult Rats

“…Furthermore, receptor down regulation due to desensitization could lead to decreased excitatory effects of substance P on respiration. Lastly, exposure to chronic intermittent hypoxia causes a decrease in NK1 receptor density on NTS neurons [34] . However, it has not been shown how chronic intermittent hypoxia affects the chemosensitive response of NTS neurons or whether chronic hypoxia affects NK1 receptor density on NTS neurons.…”