Postnatal alterations in dopaminergic markers in the human prefrontal cortex.
Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period.
Weickert
C S
CS
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 9000 Rockville Boulevard, Building 10, CRC6-5340, Bethesda, MD 20892, USA.
Webster
M J
MJ
Gondipalli
P
P
Rothmond
D
D
Fatula
R J
RJ
Herman
M M
MM
Kleinman
J E
JE
Akil
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011954:Receptors, Dopamine / Q000235:genetics*; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015415:Biomarkers; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine