Time course and magnitude of ventilatory and renal acid-base acclimatization following rapid ascent to and residence at 3,800 m over nine days.

Rapid ascent to high altitude imposes an acute hypoxic and acid-base challenge, with ventilatory and renal acclimatization countering these perturbations. Specifically, ventilatory acclimatization improves oxygenation, but with concomitant hypocapnia and respiratory alkalosis. A compensatory, renally mediated relative metabolic acidosis follows via bicarbonate elimination, normalizing arterial pH(a). The time course and magnitude of these integrated acclimatization processes are highly variable between individuals. Using a previously developed metric of renal reactivity (RR), indexing the change in arterial bicarbonate concentration (Δ[HCO3-]a; renal response) over the change in arterial pressure of CO2 (Δ[Formula: see text]; renal stimulus), we aimed to characterize changes in RR magnitude following rapid ascent and residence at altitude. Resident lowlanders (n = 16) were tested at 1,045 m (day [D]0) prior to ascent, on D2 within 24 h of arrival, and D9 during residence at 3,800 m. Radial artery blood draws were obtained to measure acid-base variables: [Formula: see text], [HCO3-]a, and pHa. Compared with D0, [Formula: see text] and [HCO3-]a were lower on D2 (P < 0.01) and D9 (P < 0.01), whereas significant changes in pHa (P = 0.072) and RR (P = 0.056) were not detected. As pHa appeared fully compensated on D2 and RR did not increase significantly from D2 to D9, these data demonstrate renal acid-base compensation within 24 h at moderate steady-state altitude. Moreover, RR was strongly and inversely correlated with ΔpHa on D2 and D9 (r≤ -0.95; P < 0.0001), suggesting that a high-gain renal response better protects pHa. Our study highlights the differential time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization following rapid ascent and residence at high altitude.NEW & NOTEWORTHY We assessed the time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization with rapid ascent and residence at 3,800 m. Despite reductions in [Formula: see text] upon ascent, pHa was normalized within 24 h of arrival at 3,800 m through renal compensation (i.e., bicarbonate elimination). Renal reactivity (RR) was unchanged between days 2 and 9, suggesting a lack of plasticity at moderate steady-state altitude. RR was strongly correlated with ΔpHa, suggesting that a high-gain renal response better protects pHa.

Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis.

In mammals, stress elicits a stereotyped endocrine response that requires an increase in the activity of hypothalamic parvocellular neuroendocrine neurons. The output of these cells is normally constrained by powerful GABA-mediated synaptic inhibition. We found that acute restraint stress in rats released the system from inhibitory synaptic drive in vivo by down-regulating the transmembrane anion transporter KCC2. This manifested as a depolarizing shift in the reversal potential of GABA(A)-mediated synaptic currents that rendered GABA inputs largely ineffective. Notably, repetitive activation of GABA synapses after stress resulted in a more rapid collapse of the anion gradient and was sufficient to increase the activity of neuroendocrine cells. Our data indicate that hypothalamic neurons integrate psychological cues to mount the endocrine response to stress by regulating anion gradients.

Brain-derived neurotrophic factor silences GABA synapses onto hypothalamic neuroendocrine cells through a postsynaptic dynamin-mediated mechanism.

In the paraventricular nucleus of the hypothalamus (PVN), experimental stress paradigms that suppress gamma-aminobutyric acid (GABA) inputs to parvocellular neuroendocrine cells (PNCs) also increase the expression of brain-derived neurotrophic factor (BDNF). In the adult CNS, BDNF regulates the efficacy of GABAergic transmission, but its contributions to functional changes at inhibitory synapses in the PVN have not been investigated. Analysis of quantal transmission revealed a decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in response to BDNF with no accompanying changes in their amplitude. These effects were completely blocked by prior inclusion of the TrKB receptor antagonist K252a in the patch pipette. Inclusion of a dynamin inhibitory peptide in the patch pipette also blocked the effects of BDNF, consistent with an all-or-none removal of clusters of postsynaptic GABAA receptors. Finally, to confirm a decrease in the availability of postsynaptic GABAA receptors, we tested the effects of BDNF on focal application of the GABAA agonist muscimol. Postsynaptic responses to muscimol were reduced after BDNF. Collectively, these data indicate that BDNF remodels functional synaptic contacts putatively by reducing the surface expression of postsynaptic GABAA receptors.

Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy.

Glial cells actively participate in synaptic transmission. They clear molecules from the synaptic cleft, receive signals from neurons and, in turn, release molecules that can modulate signaling between neuronal elements. Whether glial-derived transmitters can contribute to enduring changes in postsynaptic efficacy, however, remains to be established. In rat hypothalamic paraventricular nucleus, we demonstrate an increase in the amplitude of miniature excitatory postsynaptic currents in response to norepinephrine that requires the release of ATP from glial cells. The increase in quantal efficacy, which likely results from an insertion of AMPA receptors, is secondary to the activation of P2X(7) receptors, an increase in postsynaptic calcium and the activation of phosphatidylinositol 3-kinase. The gliotransmitter ATP, therefore, contributes directly to the regulation of postsynaptic efficacy at glutamatergic synapses in the CNS.

Dopamine modulates use-dependent plasticity of inhibitory synapses.

The release of the hormones oxytocin (OT) and vasopressin (VP) into the circulation is dictated by the electrical activity of hypothalamic magnocellular neurosecretory cells (MNCs). In the paraventricular nucleus of the hypothalamus (PVN), MNC neuronal activity is exquisitely sensitive to changes in input from inhibitory GABAergic synapses. To explore the hypothesis that efficacy at these synapses is dictated by the rate at which a given synapse is activated, we obtained whole-cell recordings from MNCs in postnatal day 21-27 male Sprague Dawley rat brain slices. IPSCs were elicited by electrically stimulating GABAergic projections from either the suprachiasmatic nucleus or putative interneuron populations immediately ventral to the fornix at 5, 10, 20, and 50 Hz. Short-term plasticity was observed at 88% of the synapses tested. Of this group, synaptic depression was observed in 58%, and synaptic facilitation was observed in 41%. Identification of cells using a combined electrophysiological and immunohistochemical approach revealed a strong correlation between cell phenotype and the nature of the plasticity. Short-term facilitation was observed preferentially in OT cells (86%), whereas short-term depression was predominant in VP neurons (69%). We next examined the effects of dopamine, which increases MNC excitability, on short-term plasticity. Activation of presynaptic D(4) receptors decreased the frequency of miniature IPSCs and prevented the development of synaptic depression at higher rates of activity. Synaptic facilitation, however, was unaffected by dopamine. These findings demonstrate that, by lowering GABA release probability, dopamine confers high-pass filtering properties to the majority of inhibitory synapses onto MNCs in PVN.