Using human postmortem brains, our studies focus on postnatal developmental changes. We examined Catechol-o-methyltansferase (COMT) enzyme activity and protein expression in the prefrontal cortex (PFC) in 6 age groups of normal individuals. COMT alters extracellular dopamine levels in PFC and its gene contains a functional polymorphism (Val158Met) that has been associated with variation in PFC function. The groups consisted of neonates (1-4 months), infants (5-11 months), teens (14-18 years), young adults (20-24 years), adults (31-43 years), and the aged (68-86 years). We found a significant increase in COMT enzyme activity from neonate to adulthood and this is paralleled by increases in protein expression. Additionally, COMT protein expression is related to the Val158Met genotype. These increases may reflect changes in the PFC dopamine system and stresses the increasing importance of COMT for PFC dopamine regulation during maturation. ? ? Our group also examined pre- and post-synaptic markers of the dopamine system in postmortem tissue across the lifespan (2 months to 86 years). We measured levels of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine biosynthesis, and we measured the three most abundant dopamine receptors (DARs) in the human PFC, DAR1, DAR2 and DAR4. We found that the mRNA levels of DAR1, DAR2, and DAR4 varied with age. The data suggests dynamic changes in these markers of the dopamine system in the human frontal cortex during postnatal development at both the pre- and post-synaptic sites. The peak increase in DAR1 mRNA levels around adolescence to early adulthood may be of particular importance to neuropsychiatric disorders, such as schizophrenia in which symptoms manifest during this developmental period. ? ? Another examination looking at neurodevelopmental changes that occur in the human brain, glucocorticoids and their receptors (GRs) are implicated in dynamic cognitive and neuroendocrine processes mediated by the PFC and hippocampus. A defect in forebrain GR levels can mimic symptoms of depression so we hypothesized that changes in GR mRNA levels may occur in human brain across lifespan thus positioning GR to differentially influence behavior and disease susceptibility. Based on this evidence, we measured levels of mRNA of GRs in the PFC and hippocampus in the human brain across 5 age groups (infants, adolescence, young adults, adults, and aged). We did not detect a main effect of age group on the hippocampus but we did see it on the cortices with the greatest expression in adolescence and adults than in infants or the aged. This suggests that human GR-mediated forebrain regulation of cognition and neuroendocrine stress response may be more apparent during late maturation and at maturity.? ? The recent identification of the NRG1 receptor, ErbB4 as a candidate risk gene for SCZ, has prompted the notion that other molecules in the NRG1 pathway maybe involved in the disorder. ErbB4 is a type 1 receptor tyrosine kinase that regulates cell growth, proliferation and differentiation. It has been shown that a molecular mechanism contributing to the genetic association of the NRG1 gene with SCZ involves altered transcriptional regulation of a novel variant of the gene. We examined ErbB4 splice variant gene expression in the hippocampus and DLPFC. ErbB4 splice patterns remain unaltered in the hippocampus in SCZ, however we observed a large increase in expression of only the splice variant containing exon 16 (JM-a) and exon 26 (CYT-1) variant isoform mRNAs in DLPFC in SCZ, suggesting that an ErbB4 receptor that contains both JM-a and CYT-1 domains is preferentially upregulated in the disease.
|Kaalund, S S; Newburn, E N; Ye, T et al. (2014) Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. Mol Psychiatry 19:1258-66|
|Montague, D; Weickert, C S; Tomaskovic-Crook, E et al. (2008) Oestrogen receptor alpha localisation in the prefrontal cortex of three mammalian species. J Neuroendocrinol 20:893-903|
|Weickert, C S; Ligons, D L; Romanczyk, T et al. (2005) Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry 10:637-50|
|Law, A J; Shannon Weickert, C; Hyde, T M et al. (2004) Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Neuroscience 127:125-36|