Activation of NR2A-Containing NMDA Receptors Is Not Obligatory for NMDA Receptor-Dependent Long-Term Potentiation

Abstract

Activation of NMDA receptors (NMDARs) within the CNS represents a major signal for persistent alterations in glutamatergic signaling, such as long-term potentiation (LTP) and long-term depression. NMDARs are composed of a combination of NR1 and NR2 subunits, with distinct NR2 subunits imparting distinct characteristics on the receptor. One particular NR2 subunit, NR2A (NRϵ1), has been proposed to play an integral role in LTP induction in the hippocampus and cortex. Here, we report studies investigating the role of NR2A in LTP induction in the dorsolateral bed nucleus of the stria terminalis (dlBNST). The putative NR2A-specific inhibitor NVP-AAM077 (AAM077) has been used previously to demonstrate the dependence of cortical and hippocampal LTP on NMDARs containing NR2A subunits. We report here the same sensitivity of LTP to pretreatment with AAM077 (0.4 μm) in the dlBNST. However, inconsistent with the conclusion that LTP in the dlBNST is NR2A dependent, we see intact LTP in the dlBNST of NR2A knock-out mice. Because we also see blockade of this dlBNST LTP in NR2A knock-out mice after pretreatment with AAM077, we conclude that the antagonist is targeting non-NR2A subunit-containing receptors. Using a variety of cultured cell types, we find that AAM077 (0.4 μm) can attenuate transmission of NR2B subunit-containing NMDARs when preapplied rather than coapplied with an agonist. Therefore, we conclude that NR2A is not obligatory for the induction of LTP in the dlBNST. Furthermore, our data demonstrate that care must be exercised in the interpretation of data generated with AAM077 when the compound is applied before an agonist.