Chronic Intermittent Hypoxia Facilitates Action Potential Firing in PVN-projecting MnPO Neurons

Abstract

Our previous results indicate that Chronic intermittent hypoxia (CIH) enhances glutamatergic neurotransmitter release in PVN-projecting MnPO neurons. Very little information exists regarding how CIH affects the excitability of PVN-projecting MnPO neurons. MnPO neurons exhibit a wide diversity of spontaneous and evoked firing patterns. Initial studies indicate CIH modulates resting membrane properties and AP firing patterns which may be associated with alterations in hyperpolarization-activated cyclic nucleotide-gated currents (Ih). The Ih current is an inward current activated by hyperpolarization from the resting potential and is an important modulator of action potential firing frequency. Data were collected in PVN-projecting MnPO neurons which play an important role in CIH-induced hypertension. Adult male Sprague Dawley rats (250-350g) received bilateral PVN injections of 200 nL retrograde adeno-associated virus pAAV-CAG-tdTomato. Three weeks following injections, rats were either exposed to a 7-day intermittent hypoxia protocol consisting of 6 min cycles (3 min 21% O2, 3 min 10% O2) repeated 10x/hr for 8 hours (during the normal inactive/sleep phase) or room air (Norm). Following CIH/Norm treatment, rats were deeply anesthetized and sagittal brain slices of MnPO were prepared using standard slice procedures. Spontaneous activity and responses to current injections were recorded from PVN projecting MnPO neurons using whole cell current-clamp. Data was analyzed off-line using Clampfit. There was a trend for spontaneous activity to be higher in PVN-projecting MnPO neurons from rats exposed to 7 days CIH when compared to normoxic controls (Norm: 2.29 ± 0.51 vs CIH: 3.3 ± 0.84) that was not due to a change in resting membrane potential. The threshold to evoke AP potentials was significantly lower in CIH neurons (5 pA injecting current, 17/19 CIH neurons vs 9/13 Norm neurons, CIH 8.6 ± 0.79 mv vs Norm 13.06±1.53 mv, p<0.01; 10 pA injecting current, 19 CIH neurons vs 12/13 Norm neurons CIH 14.74±0.92 mv vs Norm 19.72 ±1.64 mv, p<0.01). However, evoked action potentials were less sensitive to increasing current injection amplitudes in CIH vs Norm treated rats. Following bath application of the specific Ih blocker ZD7288 (ZD, 30 μm) spontaneous action potential activity was reduced by 24% in Norm neurons and 47% in CIH neurons (p=0.0313). These data demonstrate that CIH facilitates action potential generation in PVN projecting MnPO neurons and changes in Ih currents may contribute to this increase in excitability. R01 HL155977 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.