Neurotransmitters and neuromodulators during early human development

Background: Neurotransmitters such as monoamines appear in the embryo befor e the neurones are differentiated. They may have other functions than neuro transmission during embryogenesis such as differentiation and neuronal grow th. For example, serotonin may act as a morphogen. A number of neuropeptide s are expressed during ontogenesis, but their function has been difficult t o establish. Maybe some of them remain as evolutionary residues. Fast-switc hing neuro transmitters like the excitatory amino acids and the more ionotr opic receptors dominate in the human brain, but appear probably later durin g evolution as well as during ontogeny. Methods: The distribution of catech olamines during development has been analysed with a fluorescense method, w hile most of the other neuortransmitters have been mapped with immunohistoc hemical methods. The classical method to determine the physiological role o f a neurotransmitter or modulator is to study the physiological effect of i ts antagonist, blocking the endogenous activity. By transgenic technique. t he genes encoding for enzymes involved in the synthesis of neurotransmitter s can be knocked-out. Major findings: Pharmacological blocking of endogenou s activity has, for example, demonstrated that adenosine suppresses fetal r espiration. Knocking out the dopamine beta-hydroxylase gene results in feta l death, suggesting that noradrenaline is essential for survival. Some neur otransmitters change their effect during embryogenesis, e.g. GABA which is excitatory in the embryo, but inhibitory after birth due to a switch from a high to low chloride content in the nerve cells. It is possible that this is of importance for the wiring of neuronal network in early life. NMDA rec eptors dominate in the foetus, while kainate and AMPA receptors appear late r. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. Conclusions: Neurot ransmitters and modulators are not only important for the neural traffickin g in the embryo, but also for the development of the neuronal circuits. Pre natal or neonatal stress (hypoxia), as well as various drugs, may disturb t he wiring and cause long-term behavioural effects (fetal and neonatal progr amming). (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.