A functional coupling between extrasynaptic NMDA receptors and A‐type K⁺ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity

Abstract

Key pointsr In hypothalamic magnocellular neurosecretory cells, activation of glutamate NMDA receptors leads to inhibition of the transient voltage-gated A-type K + current (I A ), in a Ca 2+ -and protein kinase C-dependent manner.r The negative NMDAR-I A functional coupling involves activation of extrasynaptic (e)NMDARs.The eNMDAR-I A coupling is engaged by endogenous extracellular glutamate, whose levels are controlled by astrocyte glutamate GLT1 transporters.r The eNMDAR-I A coupling is enhanced during dehydration, a condition in which astrocyte GLT1 efficiency is blunted.r The eNMDAR-I A coupling results in increased neuronal excitability and firing activity in magnocellular neurosecretory neurons.r Taken together these studies support the concept that the eNMDAR-I A coupling is a powerful mechanism by which glutamate increases magnocellular neurosecretory excitability and firing activity.Abstract Neuronal activity is controlled by a fine-tuned balance between intrinsic properties and extrinsic synaptic inputs. Moreover, neighbouring astrocytes are now recognized to influence a wide spectrum of neuronal functions. Yet, how these three key factors act in concert to modulate and fine-tune neuronal output is not well understood. Here, we show that in rat hypothalamic magnocellular neurosecretory cells (MNCs), glutamate NMDA receptors (NMDARs) are negatively coupled to the transient, voltage-gated A-type K + current (I A ). We found that activation of NMDARs by extracellular glutamate levels influenced by astrocyte glutamate transporters resulted in a significant inhibition of I A . The NMDAR-I A functional coupling resulted from activation of extrasynaptic NMDARs, was calcium-and protein kinase C-dependent, and involved enhanced steady-state, voltage-dependent inactivation of I A . The NMDAR-I A coupling diminished the latency to the first evoked spike in response to membrane depolarization and increased the total number of evoked action potentials, thus strengthening the neuronal input/output function. Finally, we found a blunted NMDA-mediated inhibition of I A in dehydrated rats. Together, our findings support a novel signalling mechanism that involves a functional coupling between extrasynaptic NMDARs and A-type K + channels, which is influenced by local astrocytes. We show this signalling complex to play an important role in modulating hypothalamic neuronal excitability, which may contribute to adaptive responses during a sustained osmotic challenge such as dehydration.

An increased extrasynaptic NMDA tone inhibits A‐type K+ current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats

“…Our main findings could be summarized as follows: (1) as we previously reported in normal rats (Naskar & Stern, ), activation of eNMDARs by exogenously applied NMDA inhibited I A in MNCs of sham rats. However this inhibition was reduced or absent in RVH rats; (2) neither the magnitude nor the reversal potential of the exogenously evoked I NMDA was altered in RVH rats; (3) no changes in SON NMDAR subunit expression were observed between sham and RVH rats; (4) a larger endogenous glutamate tone, resulting in the sustained activation of eNMDARs, tonically inhibited I A in RVH rats, contributing also to higher ongoing firing activity during hypertension; (5) the enhanced endogenous glutamate tone in RVH rats was not due to blunted glutamate transporter activity.…”

“…; Potapenko et al . ; Naskar & Stern, ). These receptors are predominantly composed of NR1/NR2B subunits (Tovar & Westbrook, ; Li et al .…”

“…Moreover, we showed that eNMDAR activation and its coupling to I A are important in mediating homeostatic adjustments in MNC activity in response to an osmotic physiological challenge (Fleming et al . ; Naskar & Stern, ). However, whether changes in I A and NMDAR function during hypertension are functionally and/or causally interrelated through a similar mechanism remains unknown.…”

Dendritic Release of Neurotransmitters

“…In MCNs NMDARs influence overall MCN excitability and are also involved in the control of burst-firing of these cells, which optimizes hormonal release from neurohypophysial terminals (66, 86, 162, 173). Opening of NMDARs results in Ca 2+ entry and in large increases in dendritic [Ca 2+ ] i in MCNs (218, 222), with consequent dendritic release of both oxytocin (51) and vasopressin (218).…”

“…Consistent with this, functional NMDARs with unique molecular and functional properties have been found at extrasynaptic, as well postsynaptic sites (113, 207) in MCNs. Extrasynaptic NMDARs are also coupled to other Ca 2+ -dependent signaling mechanisms, including voltage-gated K + channels and ionotropic gamma-aminobutyric acid (GABA A ) receptors (162, 186, 187), unlike synaptic NMDARs. However it is not yet known whether dendritic release of neuropeptides is differentially regulated by synaptic versus extrasynaptic NMDARs.…”