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

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 (I-NMDA) 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 alpha-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 similar 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.