Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex.
Subunit composition of N-methyl-D-aspartate-type glutamate receptors (NMDARs) dictates their function, yet the ontogenic profiles of human NMDAR subunits from gestation to adulthood have not been determined. We examined NMDAR mRNA and protein development in human dorsolateral prefrontal cortex (DLPFC), an area in which NMDARs are critical for higher cognitive processing and NMDAR hypofunction is hypothesized in schizophrenia. Using quantitative reverse transcriptase-polymerase chain reaction and western blotting, we found NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function. In contrast, NR3A levels are low during gestation, surge soon after birth, and decline progressively through adolescence and into adulthood. Because NR3A subunits uniquely attenuate NMDAR-mediated currents, limit calcium influx, and suppress dendritic spine formation, high levels during early childhood may be important for regulating neuroprotection and activity-dependent sculpting of synapses. We also examined whether subunit changes underlie reduced NMDAR activity in schizophrenia. Our results reveal normal NR1 and NR3A protein levels in DLPFC from schizophrenic patients, indicating that NMDAR hypofunction is unlikely to be maintained by gross changes in NR3A-containing NMDARs or overall NMDAR numbers. These data provide insights into NMDAR functions in the developing CNS and will contribute to designing pharmacotherapies for neurological disorders.
Henson
Maile A
MA
Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC 27705, USA.
Roberts
Adam C
AC
Salimi
Kayvon
K
Vadlamudi
Swarooparani
S
Hamer
Robert M
RM
Gilmore
John H
JH
Jarskog
L Fredrik
LF
Philpot
Benjamin D
BD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*; D055815:Young Adult
D014150:Antipsychotic Agents; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C464437:NR3A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate