Mitochondria Influence NMDA Receptor‐mediated Currents in Hypothalamic Magnocellular Neurons: Altered Mechanisms during Heart Failure

Abstract

Hypothalamic magnocellular neurosecretory neurons (MNNs) located in the supraoptic (SON) and paraventricular nuclei (PVN) play a critical role in the pathophysiology of heart failure (HF). Mitochondria (MITO) plays an important role in the regulation of intracellular Ca2+ dynamics, and several studies observed that morphological and functional MITO changes contribute to the development and maintenance of various brain diseases. We recently demonstrated that NMDA receptors activation triggers a Ca2+−dependent stimulation of SK channel in MNNs from Sham rats, and that this coupling acts as a negative feedback mechanism restraining the magnitude of the NMDA receptor‐mediated current (INMDAR) and its excitatory effects. Importantly, we found that the NMDA‐SK channel coupling is blunted in MNNs from HF rats. Still, whether MITO regulation of intracellular Ca2+ dynamics influence INMDAR and whether this effect is altered during HF is unknown. To address this question, we obtained whole‐cell patch clamp recordings from MNNs (holding potential: −50 mV) in slices from Sham and HF rats. We found that focal application of NMDA (50 μM, 300 ms) evoked an INMDAR whose magnitude was similar in Sham and HF rats (p>0.05), as previously reported. Application of CCCP (10 μM, 5 s), a mitochondrial uncoupler, significantly increased the evoked INMDAR in MNNs from Sham rats (p<0.05), but had no effect in MNNs from HF rats (p>0.05). Intracellular dialysis of MNNs with the Ca2+ chelator BAPTA (10 mM) significantly augmented INMDAR in MNNs from Sham rats compared to the control condition (p<0.05), and occluded the CCCP‐induced INMDAR increase. Taken together, our data supports that mitochondria regulate, in a Ca2+‐dependent manner, the magnitude of INMDAR in MNNs from Sham rats, a phenomenon that is blunted during HF.Support or Funding InformationR01HL090948