Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

Debora A Rothmond,Maree J Webster,Cynthia S Weickert

doi:10.1186/1471-2202-13-18

Abstract

BackgroundDopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).ResultsGene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-O-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.ConclusionsWe find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

Highlights

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders
The changes in gene and protein expression during postnatal life suggest that DA neurotransmission requirements of the dorsolateral prefrontal cortex (DLPFC) vary throughout development and it may be that genes like DRD2 and MAOA may have multiple functions that vary with age
Pearson correlations with the demographic variables and the genes of interest are detailed in Table 2. pH was found to positively correlate with dopamine receptor D1 (DRD1) mRNA, DRD1 and MAOA proteins while postmortem interval (PMI) positively correlated with Dopamine receptor D2 short isoform (DRD2S), Dopamine receptor D5 (DRD5) mRNAs, and tyrosine hydroxylase (TH) protein and was negatively correlated with DRD1, MAOA, and MAOB proteins

Summary

Introduction

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The DLPFC [1,2] and adult level performance in working memory [3,4,5] may not fully mature until young of DA, in DA reception, and DA degradation were examined in this study to help define their roles during postnatal human brain development. Our laboratory measured developmental changes for tyrosine hydroxylase (TH) protein expression and DRD1, DRD2, and dopamine D4 receptor (DRD4) mRNA levels in cortical layers by in situ hybridization in the DLPFC. TH protein and DRD2 mRNA expression levels were high early in life and declined steadily with age whereas DRD1 mRNA expression was highest in young adulthood and DRD4 expression did not change significantly over the postnatal lifespan. This study did not include any individuals between the ages of 1-13 years when numerous changes in brain function occur [23,24,25] and cognitive processes are developing, in executive function [26,27]

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