Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines

Cell Rep. 2021 Jan 26;34(4):108664. doi: 10.1016/j.celrep.2020.108664.

Abstract

Experience-dependent refinement of neuronal connections is critically important for brain development and learning. Here, we show that ion-flow-independent NMDA receptor (NMDAR) signaling is required for the long-term dendritic spine growth that is a vital component of brain circuit plasticity. We find that inhibition of p38 mitogen-activated protein kinase (p38 MAPK), which is downstream of non-ionotropic NMDAR signaling in long-term depression (LTD) and spine shrinkage, blocks long-term potentiation (LTP)-induced spine growth but not LTP. We hypothesize that non-ionotropic NMDAR signaling drives the cytoskeletal changes that support bidirectional spine structural plasticity. Indeed, we find that key signaling components downstream of non-ionotropic NMDAR function in LTD-induced spine shrinkage are also necessary for LTP-induced spine growth. Furthermore, NMDAR conformational signaling with coincident Ca2+ influx is sufficient to drive CaMKII-dependent long-term spine growth, even when Ca2+ is artificially driven through voltage-gated Ca2+ channels. Our results support a model in which non-ionotropic NMDAR signaling gates the bidirectional spine structural changes vital for brain plasticity.

Keywords: CaMKII; LTD; LTP; NMDA receptor; dendritic spine; non-ionotropic; p38 MAPK; structural plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dendritic Spines / metabolism*
  • Humans
  • N-Methylaspartate / metabolism*
  • Neuronal Plasticity / physiology*
  • Receptors, N-Methyl-D-Aspartate / metabolism*

Substances

  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate