Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 May 20:2:28.
doi: 10.1186/1755-8794-2-28.

Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia

Laura W Harris  1 , Helen E Lockstone, Phillipp Khaitovich, Cynthia Shannon Weickert, Maree J Webster, Sabine Bahn
Affiliations

Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia

Laura W Harris et al. BMC Med Genomics. .

Abstract

Background: Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability".

Methods: In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25.

Results: Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence.

Conclusion: The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Template design. Subjects aged between 15 and 25 years old were assigned a value of one and all other samples a value of zero. The correlation between expression values in the 15–25 group and other samples is tested for each probe-set in turn, using Spearman rank correlation test.
Figure 2
Figure 2
Expression plots. Expression levels (log normalized; arbitrary units) versus age (years) were plotted for selected genes of interest which were significantly correlated with a template showing a peak of expression in the age range 15–25: (a) myelin component myelin binding protein (MBP) (r = 0.51, q = 0.020) (b) signaling molecule MAP kinase-1 (MAPK1) (r = -0.55, q = 0.010); (c) glucose metabolism gene acyl coA dehydrogenase (ACADSB) (r = 0.59, q = 0.008) and (d) the electron transport chain component ATP6V1E1 (r = 0.54, q = 0.014); (e) schizophrenia candidate risk factor gene neuregulin-1 (NRG1) (r = -0.59, q = 0.008); (f) ionotropic glutamate receptor subunit GRIK5 (r = -0.60, q = 0.007); (g) axon guidance molecule plexin-D1 (r = -0.56, q = 0.011). For comparison, the housekeeping gene (h) PPIA is also shown (r = 0.14, q = 0.758).
Figure 3
Figure 3
Functional profiling. Example enrichment plots are shown for categories identified using GSEA as significantly enriched in either the (a) positively or (b) negatively correlated genes. Black bars represent the position of members of the category in the ranked list, together with the running enrichment score (plotted in green). The leading edge is defined as those genes in the gene set that appear in the ranked list at, or before, the point where the enrichment score reaches its maximum deviation from zero and can be interpreted as the core of a gene set that accounts for the enrichment signal. Examples shown are (a) oxidative phosphorylation (GO:006119) q = 0.000 (b) neuron differentiation (GO:030182) q = 0.143.
Figure 4
Figure 4
Validation. (a) Quantitative real-time PCR (QPCR) validation of microarray (MA) data for 4 genes, PFKFB2, NRG1, ACADSB and MBP. Expression values shown are fold change in each of 3 age groups relative to the mean for the whole dataset. (b) Plots showing log normalized expression levels (arbitrary units) versus age (years) of two genes, NMDA receptor subunit 2B (GRIN2B) and the glucocorticoid receptor NR3C1, which show the expected expression pattern based on previous studies of the developing primate prefrontal cortex.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fuster JM. Frontal lobe and cognitive development. J Neurocytol. 2002;31:373–385. doi: 10.1023/A:1024190429920. - DOI - PubMed
    1. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF, 3rd, Herman DH, Clasen LS, Toga AW, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA. 2004;101:8174–8179. doi: 10.1073/pnas.0402680101. - DOI - PMC - PubMed
    1. Rice D, Barone S., Jr Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511–533. doi: 10.2307/3454543. - DOI - PMC - PubMed
    1. Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J. Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry. 2001;58:461–465. doi: 10.1001/archpsyc.58.5.461. - DOI - PubMed
    1. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2:861–863. doi: 10.1038/13158. - DOI - PubMed