Neural Stem Cell Abnormalities and Autism, Depression, and Schizophrenia
Neural stem cells are most abundant during early embryo development just after neural tube closure and prior to neurogenesis. The presence of fibroblast growth factor (FGF) slows down cell differentiation and can hold stem cells in stasis under laboratory conditions until needed. The levels of FGF, and various subtypes of this chemical in brain tissue continue to be investigated in light of their association with neural stem cell activity.
Neural Stem Cell Abnormalities and Mental Health
Several recent papers published on brain development and psychiatric conditions have made the association between abnormal specification, growth, expansion and differentiation or embryonic neural stem cells. Schizophrenia, autism, and both unipolar and bipolar depression have been found to be connected to disrupted or dysfunctional brain development which may result from the influence of certain genes on neural stem cell activity. The origins of many psychiatric disorders may lie right at the earliest stages of CNS development when the ‘brain’ as we know it is simply a sheet of neuroepithelial stem cells.
Sonic Hedgehog and Wingless Genes
Specific intrinsic factors which influence the neural stem cells’ differentiation and growth include FGF, Sonic Hedgehog (SHH), Bone Morphogenetic Proteins (BMP), and WNTs (the Wingless genes and Int genes). The presence and concentrations of these factors can substantially affect the CNS development, with the possibility that an imbalance can occur between excitatory and inhibitory neurons resulting in abnormal degrees of cortical circuit activation. Similarly, the variations in such factors may lead to alterations in the size or structure of different regions of the brain responsible for emotional processing, leading to difficulties with this type of cognitive action. Most of these factors exert their effects fairly early in development and decline with age, although FGF continues to be expressed in adult tissues such as the postnatal cerebral cortex and adult neural stem cell niches. This continued activity makes it a target for possible manipulation when utilizing neural stem cells for regenerative purposes in brain and CNS diseases.
How Neural Stem Cells can Explain Antidepressants’ Effects
Studies in rat embryos have shown that alterations in the expression of subtypes of FGF affects the proliferation and differentiation of neural stem cells, with FGF2, for example, leading to an increased cortex size and excitatory neuron production. Removing the FGF2 gene caused a much lower number of excitatory neurons to be created. The relationship between depression and neural stem cells is also being gradually elucidated and there is a growing body of evidence to support the notion that antidepressants may actually work in part by influencing the levels and expression of FGF2 in neurones and astrocytes, thereby affecting cognitive turnover and activity (Malberg, et al, 2000, Turner, et al, 2008, Boldrini, et al, 2009).
References
Kimiskidis, V., Fassas, A., Sakellari, I., Kapinas, K.m Anagnostopoulos, A., Tsimourtou, V., Sotirakoglou, K., Kazis, A., (2011), Long-term results of stem cell transplantation for MS, Neurology, Vol.76, no.12, pp.1066-1070. http://www.neurology.org/content/76/12/1066.full
Weiner, L.P., (2008), Neural stem cells: methods and protocols: Volume 438, Springer.
Zigova, T., Sanberg, P.R., Sanchez-Ramos, J.R., (2002), Neural Stem Cells: Methods and Protocols, Humana Press.
Stevens, H.E., Smith, K.M., Rash, B.G., Vaccarino, F.M., (2010), Neural Stem Cell Regulation, Fibroblast Growth Factors, and the Developmental Origins of Neuropsychiatric Disorders, Frontiers in Neuroscience., Vol.4, p.59.
Boldrini M., Underwood M. D., Hen R., Rosoklija G. B., Dwork A. J., John Mann J., Arango V. (2009). Antidepressants increase neural progenitor cells in the human hippocampus.Neuropsychopharmacology 34, 2376–2389.
Ma D. K., Bonaguidi M. A., Ming G. L., Song H. (2009a). Adult neural stem cells in the mammalian central nervous system. Cell Res. 19, 672–682.
Malberg J. E., Eisch A. J., Nestler E. J., Duman R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110.
Turner C. A., Gula E. L., Taylor L. P., Watson S. J., Akil H. (2008). Antidepressant-like effects of intracerebroventricular FGF2 in rats. Brain Res. 1224, 63–68.
