Postnatal Development of NMDA Receptors in an Immature Inhibitory Circuit

Abstract

For optimal function, neural circuits require precise connectivity. Neural circuits achieve this precision through developmental refinement that typically takes place in early postnatal life. N-methyl-D-aspartate receptors (NMDARs) are known mediators of developmental refinement in many glutamatergic circuits and are hypothesized to mediate refinement in glutamate-releasing immature inhibitory circuits of the superior olivary complex (SOC). Physiological studies in the SOC have shown that NMDAR activity is high at birth, occurs primarily through NMDARs that contain the GluN2B subunit, and decreases rapidly over the first two postnatal weeks. These studies did not distinguish whether the decrease in GluN2B-mediated NMDAR activity could be due to a subunit substitution or an overall reduction in NMDAR expression. Using fluorescent in situ hybridization and immunohistochemistry, I assessed the expression of NMDAR subunits during early postnatal development in the rat SOC’s primary and periolivary nuclei: the lateral superior olive, the medial superior olive, the medial nucleus of the trapezoid body, the ventral nucleus of the trapezoid body, the lateral nucleus of the trapezoid body, and the superior periolivary nucleus. I found that all NMDAR subunit transcripts decreased between postnatal days 0 and 28 in all nuclei. All subunits in the GluN2 subunit family – GluN2A, GluN2B, GluN2C, and GluN2D – showed varying expression patterns, which are consistent with a subunit substitution. These results suggest the involvement of different NMDAR subtypes during circuit refinement in glutamate-releasing immature inhibitory circuits and a decline in NMDARs when the circuit reaches its mature state. The developmental profile of NMDARs might suggest the events taking place during refinement.