Dooley, Audrey Elaine; (1997) The role of serotonin and other neurotransmitter substances in the development of cortical cell types: An in vitro study. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The different neuronal and glial cell types that form the mammalian cerebral cortex are generated from a population of epithelial cells lining the embryonic telencephalic ventricles. Cells within this germinal layer proliferate and migrate to form the characteristic six-layered structure of the neocortex. The factors that control the proliferation of cortical progenitor cells and their differentiation into different cell types are still mainly unknown, but recent studies point to the importance of signals from the cells' microenvironment in their commitment to a particular phenotype and laminar fate. Such signals may be provided by growth factors, hormones, neuropeptides, extracellular matrix molecules, or neurotransmitters produced and regulated locally by differentiated cortical neurons or afferent axonal systems. A host of neurotransmitters have been implicated in regulating the proliferation and differentiation of cortical cell types. Chief among them are the catecholamines, noradrenaline and dopamine, and the indoleamine, 5-hydroxytryptamine (serotonin; 5-HT). The early development of the monoaminergic systems has prompted speculation that they may play a role in a number of developmental processes in the cortex. In this study I focused on the role of 5-HT during the prenatal period of cortical development by using primary cultures of dissociated neocortex established from embryonic day 14 (E14), E16, and E18 rats. These cultures were grown in defined medium, or additionally exposed to 5-HT and examined for survival effects during 1-11 days m vitro (DIV). 5-HT significantly increased survival of these cultures in a concentration dependent manner. E14 cultures showed a 1.3-fold increase at 9 DIV, E16 cultures a 2-4-fold increase between 7-9 DIV and El8 cultures a 1.6-2.2-fold increase from 2-4 DIV. This survival was mimicked by the 5-HT 2a/2c receptor agonist a-methyl-5-HT, but not by the 5-HT1a receptor agonist 8-hydroxy-2(di-n-propylamino) tetralin. Survival was predominantly of postmitotic neurons immunopositive for microtubule- associated protein (MAP-2). The other monoamines noradrenaline (NA) and dopamine (DA) also had a survival effect on developing cortical cell types in contrast to the neurotransmitters γ-amino butyric acid (GABA) and acetylcholine (ACh). In conclusion, these results indicate the importance of 5-HT and other neurotransmitter substances in the survival of cortical cells during development and point to a preferential survival of postmitotic cortical neurons.

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