NMDA receptors promote survival in somatosensory relay nuclei by inhibiting Bax-dependent developmental cell death.
Naturally occurring cell death is a universal feature of developing nervous systems that plays an essential role in determining adult brain function. Yet little is known about the decisions that select a subset of CNS neurons for survival and cause others to die. We report that postnatal day 0 NMDA receptor subunit 1 (NMDAR1) knockout mice display an approximately 2-fold increase in cell death in the brainstem trigeminal complex (BSTC), including all four nuclei that receive somatosensory inputs from the face (principalis, oralis, interpolaris, and caudalis). Treatment with the NMDA receptor antagonist dizocilpine maleate (MK-801) for 24 h before birth also caused an increase in cell death that reached statistical significance in two of the four nuclei (oralis and interpolaris). The neonatal sensitivity to NMDA receptor hypofunction in the BSTC, and in its main thalamic target, the ventrobasal nucleus (VB), coincides with the peak of naturally occurring cell death and trigeminothalamic synaptogenesis. At embryonic day 17.5, before the onset of these events, NMDAR1 knockout does not affect cell survival in either the BSTC or the VB. Immunostaining for active caspase-3 and the neuronal marker Hu specifically confirms the presence of dying neurons in the BSTC and the VB of NMDAR1 knockout neonates. Finally, genetic deletion of Bax rescues these structures from the requirement for NMDA receptors to limit naturally occurring cell death. Taken together, the results indicate that NMDA receptors play a survival role for somatosensory relay neurons during synaptogenesis by inhibiting Bax-dependent developmental cell death.
de Rivero Vaccari
Juan Carlos
JC
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Casey
Gregory P
GP
Aleem
Salman
S
Park
Won-Mee
WM
Corriveau
Roderick A
RA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002470:Cell Survival / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013003:Somatosensory Cortex / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D014278:Trigeminal Nuclei / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D016291:Dizocilpine Maleate; D016194:Receptors, N-Methyl-D-Aspartate; D051028:bcl-2-Associated X Protein; C494827:Bax protein, mouse