Korean J Physiol Pharmacol.  2016 Jul;20(4):425-432. 10.4196/kjpp.2016.20.4.425.

Facilitation of AMPA receptor-mediated steady-state current by extrasynaptic NMDA receptors in supraoptic magnocellular neurosecretory cells

• Pai YH
• Lim CS
• Park KA
• Cho HS
• Lee GS
• Shin YS
• Kim HW
• Jeon BH
• Yoon SH
• Park JB

• KMID: 2371060
• DOI: http://doi.org/10.4196/kjpp.2016.20.4.425

Abstract

In addition to classical synaptic transmission, information is transmitted between cells via the activation of extrasynaptic receptors that generate persistent tonic current in the brain. While growing evidence supports the presence of tonic NMDA current (INMDA) generated by extrasynaptic NMDA receptors (eNMDARs), the functional significance of tonic I(NMDA) in various brain regions remains poorly understood. Here, we demonstrate that activation of eNMDARs that generate I(NMDA) facilitates the α-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor (AMPAR)-mediated steady-state current in supraoptic nucleus (SON) magnocellular neurosecretory cells (MNCs). In low-Mg2+ artificial cerebrospinal fluid (aCSF), glutamate induced an inward shift in I(holding) (I(GLU)) at a holding potential (V(holding)) of -70 mV which was partly blocked by an AMPAR antagonist, NBQX. NBQX-sensitive I(GLU) was observed even in normal aCSF at V(holding) of -40 mV or -20 mV. I(GLU) was completely abolished by pretreatment with an NMDAR blocker, AP5, under all tested conditions. AMPA induced a reproducible inward shift in I(holding) (I(AMPA)) in SON MNCs. Pretreatment with AP5 attenuated I(AMPA) amplitudes to ~60% of the control levels in low-Mg2+ aCSF, but not in normal aCSF at V(holding) of -70 mV. I(AMPA) attenuation by AP5 was also prominent in normal aCSF at depolarized holding potentials. Memantine, an eNMDAR blocker, mimicked the AP5-induced I(AMPA) attenuation in SON MNCs. Finally, chronic dehydration did not affect I(AMPA) attenuation by AP5 in the neurons. These results suggest that tonic I(NMDA), mediated by eNMDAR, facilitates AMPAR function, changing the postsynaptic response to its agonists in normal and osmotically challenged SON MNCs.

Keyword

AMPA receptors; Chronic dehydration; Extrasynaptic NMDA receptors; Magnocellular neurosecretory cells

MeSH Terms

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid*
Brain
Cerebrospinal Fluid
Dehydration
Glutamic Acid
Memantine
N-Methylaspartate*
Neurons
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate*
Supraoptic Nucleus
Synaptic Transmission
Glutamic Acid
Memantine
N-Methylaspartate
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Figure

• 

  Fig. 1 Glutamate evoked NBQX-sensitive tonic currents in an NMDAR activation-dependent manner in SON MNCs.(A) Representative current traces showing that IGLU was blocked by the sequential application of NBQX (IAMPA) and NBQX+AP5 (INMDA) in low-Mg2+ aCSF. (B) The mean IAMPA and INMDA in the absence (n=7) and presence (n=3) of AP5 are summarized as in A. (C) Representative current traces showing that glutamate evoked IAMPA in an INMDA-dependent manner at depolarized holding potentials in normal aCSF. Note that IGlu was efficiently blocked by AP5 alone, which was not affected by picrotoxin (inset, Vholding of –40 mV in normal aCSF). (D) The mean IAMPA and INMDA at different holding potentials (n=3~7) are summarized as in C. ***p<0.001 compared to each control.

• 

  Fig. 2 NMDAR activation facilitated AMPA-induced steady-state inward currents (IAMPA) in SON MNCs.(A) Representative current traces showing IAMPA in low and normal Mg2+ aCSF (Vholding –70 mV). Note that pretreatment with AP5 consistently reduced IAMPA in low-Mg2+ aCSF, while repeated applications of AMPA increased IAMPA in normal aCSF. Bold lines at each trace represent the application of an AMPAR antagonist, DNQX or NBQX. (B) The mean IAMPA amplitudes in low-Mg2+ (n=12) and normal (n=10) aCSF are summarized as in A. Effects of AP5 on the first and second IAMPA were tested and combined from the same number of neurons in each group. (C) Representative current traces showing that the pretreatment of AP5 consistently reduced IAMPA recorded at Vholding of –40 mV in normal aCSF. IAMPA inhibition by AP5 was not affected by picrotoxin in normal aCSF (Vholding –20 mV, inset). Bold lines at each trace represent the application of AMPAR antagonist as in A. (D) The mean IAMPA amplitudes at Vholding of –40 mV (n=12) and –20 mV (n=10) are summarized. Effects of AP5 on the first and second IAMPA were pooled as in B. ***p<0.001 compared to respective controls.

• 

  Fig. 3 Extrasynaptic NMDARs mediate IAMPA facilitation in SON MNCs.(A) Representative current traces showing that the extrasynaptic NMDAR antagonist, memantine (MEM), attenuated IAMPA in low-Mg2+ aCSF (Vholding –70 mV). (B) Effects of memantine on IAMPA amplitude in low-Mg2+ aCSF (Vholding –70 mV, n = 8) and normal aCSF (Vholding –40 mV, n = 6) are summarized. Effects of MEM on the first and second IAMPA were pooled as in Fig. 2. ***p<0.001 compared to respective control.

• 

  Fig. 4 IAMPA facilitation by NMDAR in SON MNCs from chronically dehydrated (DE) rats.Inhibition of IAMPA by AP5 was compared in euhydrated (EU) and DE SON MNCs. AP5 inhibited IAMPA at similar rates in DU and DE SON MNCs.

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