ZFIN ID: ZDB-PUB-180517-3
The Midline Axon Crossing Decision Is Regulated through an Activity-Dependent Mechanism by the NMDA Receptor
Gao, J., Stevenson, T.J., Douglass, A.D., Barrios, J.P., Bonkowsky, J.L.
Date: 2018
Source: eNeuro   5(2): (Journal)
Registered Authors: Bonkowsky, Joshua, Gao, Jingxia
Keywords: NMDA receptor, activity, axon pathfinding, hypoxia, midline, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Axons/physiology*
  • Central Nervous System/embryology*
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental/physiology*
  • Hypoxia/metabolism
  • Receptors, N-Methyl-D-Aspartate/metabolism
  • Receptors, N-Methyl-D-Aspartate/physiology*
  • Zebrafish
  • Zebrafish Proteins
PubMed: 29766040 Full text @ eNeuro
Axon guidance in vertebrates is controlled by genetic cascades as well as by intrinsic activity-dependent refinement of connections. Midline axon crossing is one of the best studied pathfinding models and is fundamental to the establishment of bilaterally symmetric nervous systems. However, it is not known whether crossing requires intrinsic activity in axons, and what controls that activity. Further, a mechanism linking neuronal activity and gene expression has not been identified for axon pathfinding. Using embryonic zebrafish, we found that the NMDA receptor (NMDAR) NR1.1 subunit (grin1a) is expressed in commissural axons. Pharmacological inhibition of grin1a, hypoxia exposure reduction of grin1a expression, or CRISPR knock-down of grin1a leads to defects in midline crossing. Inhibition of neuronal activity phenocopies the effects of grin1a loss on midline crossing. By combining pharmacological inhibition of the NMDAR with optogenetic stimulation to precisely restore neuronal activity, we observed rescue of midline crossing. This suggests that the NMDAR controls pathfinding by an activity-dependent mechanism. We further show that the NMDAR may act, via modulating activity, on the transcription factor arxa (mammalian Arx), a known regulator of midline pathfinding. These findings uncover a novel role for the NMDAR in controlling activity to regulate commissural pathfinding and identify arxa as a key link between the genetic and activity-dependent regulation of midline axon guidance.