The Unit on Molecules in Neurobiology for the Development of Schizophrenia (MiNDS) is part of the Section on Neuropathology in the Clinical Brain Disorders Branch, which utilizes molecular biological methodologies in brain to elucidate the neurobiology and pathophysiology of schizophrenia. In collaboration with the Section of Neuropathology, we are able to obtain well-characterized human brain samples from healthy persons and those with schizophrenia, allowing us to explore the molecular neurodevelopmental changes that occur in the human brain from infancy through adulthood. Understanding normal gene expression changes may provide clues to the underlying neurobiological events that lead to behavioral changes that are associated with schizophrenia and other major mental illnesses. We have successfully charted molecular neurobiological changes in the levels of growth-related factors, such as neurotrophic factors, dopamine receptors, and hormone receptors across normal development and compared levels of these developmentally important molecules in samples from patients with schizophrenia compared to age-matched controls. It appears that the onset of psychiatric symptoms coincides with diverse molecular changes in frontal cortex gene expression and with human behavioral maturation. While 1% of the general population suffers from schizophrenia, little is known about the cause of this complex brain disorder; but we do know that there is there is a genetic risk for developing schizophrenia that is influenced by environment or neurobiological events. One way the environment impacts the genes is by changing their expression levels across time; therefore, we study genes across neurodevelopment. It is our hypothesis that patients with schizophrenia fail to undergo the correct cellular and molecular changes that occur in the normal human brain during human maturation. Specifically, our projects include: 1) how """"""""schizophrenia"""""""" genes influence the development of brain cells; 2) how variations of the estrogen receptor (ER) impact the development and function of the cerebral cortex; and 3) how neuregulin-1 (NRG-1) in particular may change its expression across postnatal development and how precisely the gene is changed in patients with schizophrenia. One of our first studies explored the anatomical distribution of growth factor, NRG-1 in human adult brain samples; we show messenger ribonucleic acid (mRNA) expression is widespread in cell populations, specifically neuronal and glia cells which are implicated in schizophrenia. Our next step is to map particular forms of the NRG-1 mRNA as we have determined that only some forms of the gene have altered expression levels, but we do not know if the cellular distribution of the unaltered or altered forms is anatomically normal in patients with schizophrenia. The continuous gene expression of NRG-1 in the adult brain may suggest that it has a functional role in maintenance of neural cells. We are also finding the most abundant NRG-1 mRNA in human infants suggesting that it may have a more salient role early in postnatal life. We will further discern the role of NRG-1, as it pertains to schizophrenia and other major brain disorders in which it may be pathophsyiologically implicated by examining the NGR-1 receptors ErbB2, ErbB3, and ErbB4. Another important growth factor we studied is the basic fibroblast growth factor (bFGF), which is present in early brain development, influences the size of the cerebral cortex, cell proliferation, survival, and neuronal density in the hippocampus. Our findings show that bFGF and its receptor FGFR1 are present in many regions of the adult human brain again, like NRG-1 this suggests an ongoing role in maintenance of brain cells. In the adult human brain, most of the pyramidal neurons are responsive to FGF and continue to produce FGFR1 mRNA and protein. We also have shown that adult cell proliferation in the subependymal zone, a specialized area deep in the brain where neurons are born throughout life, can be doubled when we inject bFGF into an adult monkey. It is not known how bFGF or FGFR1 may be altered in brains of patients with schizophrenia. Our group also examined the role of ER-alpha expression in the amygdala of patients with a major mental illness. The goal was to study the stress response and regulation of emotional behaviors, processes which are abnormal and are characteristics of patients with neuropsychaitric illnesses. The amygdala, a limbic structure in the brain, is critical for the neuronal response to stress. Glucocorticoids are known mediators of the stress response, and therefore the glucocorticoids receptor (GR) mRNA levels may be altered in the amygdala leading us to hypothesize that the levels of ER-alpha mRNA may also be altered in the amygdala. Our data shows that GR mRNA is altered in regionally and diagnostically specific ways, challenging the premise that high glucocorticoid levels indiscriminately suppress GR mRNA in all regions of the brain in patients with mental illness. In other words, the molecular changes we find are not consistent with the idea that the stress associated with having a severe mental illness is the only reason that GR mRNA is reduced, rather it suggests that GR alterations my be causing the altered ability of these patients to respond to stressful events. Another goal was to examine different variations of the ER-alpha mRNA in human and primate PFC to further characterize the neuronal responses to estrogens. Through examination of the ER-alpha variants in the frontal cortex, we can possibly begin to define all the possible molecular routes by which estrogen can impact neuronal cells in humans. This is important as we know sex-steroid levels not only trigger brain maturation at puberty, but also modify the symptoms of psychiatric symptoms, but we do not understand how testosterone and estrogen regulate development and symptoms. Our group studied neurotrophins, which regulate neuronal numbers and connections during development and maturation in the dorsolateral prefrontal cortex (DLPFC). Growth-promoting effects of neurotrophins are mediated through tyrosine-kinase receptors (trkB and trkC). Brain-derived neurotrophic factor (BDNF) had reduced levels in the DLPFC of patients with schizophrenia. A reduction in cortically derived neurotrophins may have a direct effect on neighboring cortical neurons. Therefore, we theorized that an altered level of neurotrophin receptor may exist in DLPFC in patients with schizophrenia. We measured the levels of trkB and trkC in schizophrenic and control tissue samples and found widespread reduction in neurotrophic receptor gene expression in the neurons of the DLPFC of the patients with schizophrenia. The reduction in receptor synthesis may then reduce the ability of neurons in the frontal cortex to respond to neuronal growth factors in schizophrenia. We have also discovered that the most abundant trk receptor, trkC has two major isoforms, full-length protein and truncated protein. While the full-length protein is detected at low levels during brain development, the truncated protein is expressed at moderate levels early in development and increases to mature levels by adolescence. However, the mRNA levels are consistently expressed during postnatal life, but decline with ageing suggesting independent regulatory pathways. The truncated trkC protein and mRNA are expressed in both pyramidal and non-pyramidal neurons while, trkC protein is found in glia, and synaptic fields suggesting responsiveness of the human brain to neutrophin-3, a potent neutrophin throughout life. Since we found that trkC mRNA is reduced in the brains of patients with schizophrenia, we are currently looking at trkC protein and NT-3 levels to determine if they are altered in the diseased brain.
| 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 |
