In addition to producing a classical excitatory postsynaptic current via activation of synaptic NMDA receptors (NMDARs), glutamate in the brain also induces a tonic NMDAR current (I NMDA ) via activation of extrasynaptic NMDARs (eNMDARs). However, since Mg 21 blocks NMDARs in nondepolarized neurons, the potential contribution of eNMDARs to the overall neuronal excitatory/inhibitory (E/I) balance remains unknown. Here, we demonstrate that chronic (7 d) salt loading (SL) recruited NR2D subunitcontaining NMDARs to generate an Mg 21 -resistant tonic I NMDA in nondepolarized [V h (holding potential) 270 mV] vasopressin (VP; but not oxytocin) supraoptic nucleus (SON) neurons in male rodents. Conversely, in euhydrated (EU) and 3 d SL mice, Mg 21 -resistant tonic I NMDA was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg 21resistant tonic I NMDA in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg 21 -sensitive tonic I NMDA but not Mg 21 -resistant tonic I NMDA . In the EU group VP neurons, an Mg 21 -resistant tonic I NMDA was not generated by increased ambient glutamate or treatment with coagonists (e.g., D-serine and glycine). Chronic SL significantly increased NR2D expression but not NR2B expression in the SON relative to the EU group or after 3 d under SL conditions. Finally, Mg 21 -resistant tonic I NMDA selectively upregulated neuronal excitability in VP neurons under SL conditions, independent of ionotropic GABAergic input. Our results indicate that the activation of NR2D-containing NMDARs constitutes a novel mechanism that generates an Mg 21 -resistant tonic I NMDA in nondepolarized VP neurons, thus causing an E/I balance shift in VP neurons to compensate for the hormonal demands imposed by a chronic osmotic challenge.
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