Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions

Stephanie Jacobs, Zhenzhong Cui, Ruiben Feng, Huimin Wang, Deheng Wang, Joe Z. Tsien

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced longterm potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range.

Original languageEnglish (US)
Article numbere111865
JournalPloS one
Volume9
Issue number10
DOIs
StatePublished - Oct 31 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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