Neurotransmitters and neuromodulators during early human development

Abstract

Background: Neurotransmitters such as monoamines appear in the embryo before the neurones are differentiated. They may have other functions than neurotransmission during embryogenesis such as differentiation and neuronal growth. For example, serotonin may act as a morphogen. A number of neuropeptides are expressed during ontogenesis, but their function has been difficult to establish. Maybe some of them remain as evolutionary residues. Fast-switching neurotransmitters like the excitatory amino acids and the more ionotropic receptors dominate in the human brain, but appear probably later during evolution as well as during ontogeny. Methods: The distribution of catecholamines during development has been analysed with a fluorescense method, while most of the other neuortransmitters have been mapped with immunohistochemical methods. The classical method to determine the physiological role of a neurotransmitter or modulator is to study the physiological effect of its antagonist, blocking the endogenous activity. By transgenic technique, the genes encoding for enzymes involved in the synthesis of neurotransmitters can be knocked-out. Major findings: Pharmacological blocking of endogenous activity has, for example, demonstrated that adenosine suppresses fetal respiration. Knocking out the dopamine beta-hydroxylase gene results in fetal death, suggesting that noradrenaline is essential for survival. Some neurotransmitters 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 receptors dominate in the foetus, while kainate and AMPA receptors appear later. At birth, there is a surge of neurotransmitters such as catecholamines, which may be of importance for the neonatal adaptation. Conclusions: Neurotransmitters and modulators are not only important for the neural trafficking in the embryo, but also for the development of the neuronal circuits. Prenatal or neonatal stress (hypoxia), as well as various drugs, may disturb the wiring and cause long-term behavioural effects (fetal and neonatal programming).

Introduction

Although genes mainly determine the development of the scaffold of the CNS, the detailed wiring of the neuronal circuits is to a large degree self-generated dependent on the action of neurotransmitters and neuromodulators. They can promote, amplify, block, inhibit or attenuate the micro-electric signals which are passed on to neurones. Thereby, they give rise to the signalling patterns between myriads of neuronal networks providing the physical networks of cerebral neurones. Neurotransmitters such as the catecholamines appear in the embryos of vertebrate and invertebrate animals even before neurones are differentiated [1]. Some of the cells in the neuronal crest contain noradrenaline from the outset, but become cholinergic due to environmental influences [2].

Many neuroactive molecules change their functional role in the CNS during development. The same molecule may be crucial for differentiation, neuronal growth and establishment of neuronal networks in the immature CNS while switching to a more modulatory role of the ongoing traffic in the mature CNS. Receptor subunits may exchange during development, i.e. the NMDA receptors, whose subunits allow longer open channel time during early development then switch to a shorter, more stable adult subunit composition. This is of importance for the plasticity of the immature brain and subsequently, for memory storage and preservation in the adult brain [3].

Noradrenaline and acetylcholine are regarded as classical neurotransmitters and dominate in the peripheral nervous system (Fig. 1). They appear at an early stage during both phylogenesis and ontogenesis. Many of the neuropeptides were first identified in the gastrointestinal tract and probably appear early during CNS development. They act slowly since they have to be synthesised and packaged in the cell soma and carried to the terminals before they can be released. The recently evolved and more sophisticated mammalian brain requires more fast-switching neurotransmitters acting directly on ion-channels. Therefore, excitatory and inhibitory amino acids seem to dominate in the mature CNS, where the monoamines and neuropeptides may act more as neuromodulators (see Ref. [4]).

The distinction between a transmitter and a modulator is far from clear, since several of the neuroactive agents described to date change their role during brain development or have different actions depending on brain region or innervated neurones. Furthermore, a given transmitter may have different effects depending on brain region, postsynaptic receptor configuration, G-protein coupling and second messenger system.

A neuroactive agent can be expressed in high amounts during certain stages of development, but then persists in only a few synapses [5]. It is possible that this agent either has only a transitory role in a critical window in development or that it remains mainly as an evolutionary residue, with minor functions in, e.g. mammals. If the synthesis of some of these neurotransmitters/modulators is blocked pharmacologically or knocked-out by transgenic techniques, it does not seem to affect survival or even important physiological functions. This illustrates the plasticity of the brain during early development. Other neuroactive agents seem to be able to take over. Markers for neurotransmitters and neuromodulators during CNS development generally appear first in the caudal and phylogenetically older part of the brain probably due to earlier neurogenesis (see Ref. [6]).

Classification of the main neurotransmitters and modulators according to principal biochemical differences and tentative ontogenetic appearance is depicted in Table 1.