Differing, spatially restricted roles of ionotropic glutamate receptors in regulating the migration of GnRH neurons during embryogenesis

We have examined here the role of glutamate in regulating the process of tangential neuronal migration during embryogenesis by investigating the roles of AMPA and NMDA receptors in the migration of the gonadotropin-releasing hormone (GnRH) neurons from the nose to the hypothalamus. We first determined that GluR1-4 subunit mRNAs were present from embryonic day (E) 12.5 along the complete nose-brain migratory pathway of the GnRH neurons, whereas that of the obligatory NMDAR1 transcript was present only in brain regions of GnRH migration. In vivo studies revealed that AMPA receptor antagonism between E12.5 and E16.5 resulted in a significant (p < 0.05) accumulation of GnRH neurons in the nose adjacent to the cribiform plate. In contrast, NMDA receptor antagonism over E12.5-E16.5 or E13.5-E16.5 caused a selective increase ( p, 0.05) in the number of GnRH neurons located in their final resting place within the diagonal band of Broca and preoptic area. Dual-labeling studies using GnRH promoter-LacZ transgenic mice, which facilitate the identification of receptors in GnRH neurons, identified the presence of NMDAR1 receptors in <similar to>6% of embryonic GnRH neurons located throughout the migratory pathway. Postnatally, the percentage of GnRH neurons expressing NMDAR1 increased to 50%. These results indicate that tonic AMPA receptor activation enhances the migration of GnRH neurons from the nose into the brain, whereas that of NMDA receptor activation slows the final phase of GnRH migration within the forebrain. These in vivo observations demonstrate differing, spatially restricted roles for AMPA and NMDA receptor activation in the process of tangential neuronal migration.