FUNCTIONAL RESPIRATORY RHYTHM GENERATING NETWORKS IN NEONATAL MICE LACKING NMDAR1 GENE

N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission is implicated in activity-dependent developmental reorganization in mamm alian brain, including sensory systems and spinal motoneuron circuits. During normal development, synaptic interactions important in activit y-dependent modification of neuronal circuits may be driven spontaneou sly (Shatz 1990b). The respiratory system exhibits substantial spontan eous activity in utero; this activity may be critical in assuring esse ntial and appropriate breathing movements from birth. We tested the hy pothesis that NMDA receptors are necessary for prenatal development of central neural circuits underlying respiratory rhythm generation by c omparing the responsiveness of control mice and mutant mice lacking th e NMDA receptor R1 subunit (NMDARI) gene to glutamate receptor agonist s and antagonists and comparing endogenous respiratory-related oscilla tions generated in vitro by brain stem-spinal cord and medullary slice preparations from control and mutant mice. In control mice, local app lication of NMDA and the non-NMDA receptor agonist, pha-amino-3-hydrox y-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA), over the pr e-Botzinger Complex, the C4 cervical motor neuron pool, and the hypogl ossal motor nucleus produced profound increases in inspiratory frequen cy, tonic discharge on C4 ventral nerve roots, and inward currents in inspiratory hypoglossal motoneurons, respectively. Responses of mutant mice to AMPA were similar. However, mutant mice were completely unres ponsive to NMDA applications. Preparations from mutant mice generated a respiratory rhythm virtually identical to control. Results demonstra te that NMDA receptors are not essential for respiratory rhythm genera tion or drive transmission in the neonate. More importantly, they sugg est that NMDA receptors are not obligatory for the prenatal developmen t of circuits producing respiratory rhythm.