ABSTRACTGlutamatergic NMDA receptors (NMDAR) and small conductance Ca2+-activated K+ channels (SK) are critical synaptic and intrinsic mechanisms that regulate the activity of hypothalamic magnocellular neurosecretory neurons (MNNs) under physiological and pathological states, including lactation and heart failure (HF). Still, whether NMDARs and SK channels in MNNs are functionally coupled, and whether changes in this coupling contribute to exacerbated neuronal activity during HF is at present unknown. In the present study, we addressed these questions using patch-clamp electrophysiology and confocal Ca2+ imaging in a rat model of ischaemic HF. We found that in MNNs of sham rats, blockade of SK channels with apamin (200 nM) significantly increased the magnitude of an NMDAR-evoked current (INMDA). We also observed that blockade of SK channels potentiated NMDAR-evoked firing, and abolished spike frequency adaptation in MNNs from sham, but not HF rats. Importantly, a larger INMDA-ΔCa2+response was observed under basal conditions in HF compared to sham rats. Finally, we found that dialyzing recorded cells with the Ca2+ chelator BAPTA (10 mM) increased the magnitude of INMDA in MNNs from both sham and HF rats, and occluded the effects of apamin in the former. Together, our studies demonstrate that in MNNs, NMDARs and SK channels are functionally coupled, forming a local negative feedback loop that restrains the excitatory effect evoked by NMDAR activation. Moreover, our studies also support a blunted NMDAR-SK channel coupling in MNNs of HF rats, standing thus as a pathophysiological mechanism contributing to exacerbated hypothalamic neuronal activity during this prevalent neurogenic cardiovascular disease.
A functional coupling between extrasynaptic NMDA receptors and A-type K+channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity