Trophic Effects of Neurotransmitters during Brain Maturation

Abstract

Besides their neurotransmitter and/or neuromodulatory roles, many neuroactive substances synthesized and released during brain development can also directly influence neuronal differentiation. Transitory expression of neurotransmitters, their metabolic enzymes and their receptors is only one aspect of this trophic role. The most considerable progress in neurotrophic factor research has been made with the use of primary cultures of neuronal cells, and numerous studies have focused on the effects of neurotransmitters on the differentiation of cells at various stages of development. Thus, several neuropeptides like VIP, substance P, enkephalins, somatostatin, and monoamines, can modulate neuronal differentiation, but only during a limited period of fetal life. Among the monoamines, it was shown that, depending on the target, 5-HT stimulates the development of the neuropile, the myelinization of axons, the differentiation of the synaptic contacts, induces markers of monoaminergic neuron differentiation, inhibits the development of the growth cone, decreases the branching of neurites, and influences the survival, cell body size, and neurite outgrowth in several neuronal cultures. 5-HT can also indirectly influence the differentiation of serotonergic neurons by the intermediate of astrocytes, and it was shown in our laboratory that 5-HT_1A agonists can stimulate the cholinergic parameters of primary cultures of rat fetal septal neurons. At the molecular level, the events triggered by neurotransmitters that underlie their neurotrophic action probably involve the transmembrane influx of calcium. To date, calcium regulation of cellular processes is one of the most rapidly expanding areas of research in developmental neurobiology.

Selective neuronal toxicity of cocaine in embryonic mouse brain cocultures.

“…Molecules as diverse as extracellular matrix constituents (46), growth factors (47), neurotransmitters (48), and proteases or their inhibitors can exert dramatic effects, ranging from stimulation of neurite outgrowth to induction of neurite retraction and growth cone collapse (49). Astroglial cells are also key contributors to brain development by releasing a number of growth factors and extracellular matrix constituents such as laminin and fibronectin, all of which stimulate neuronal proliferation and promote axonal spreading (50).…”

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

“…However, various lines of evidence suggest that neurotransmitters may have several important roles in brain development in addition to neurotransmission (Buznikov, 1984;Lauder, 1988;Emerit et al, 1992;Johnston, 1995;Retz et al, 1996;Levitt et al, 1997;Contestabile, 2000;Nguyen et al, 2001). First, the appearance of one or more key components of neurotransmission may precede synaptogenesis; for example GABA, glutamate decarboxylase (GAD), and GABA A receptors are present in embryonic neurons well before the development of GABAergic synapses (Kim et al, 1996).…”

“…Neurotransmitters can also act as trophic factors modulating the apoptotic processes that are known to occur at certain stages of brain development (Emerit et al, 1992;Ikonomidou et al, 2001). Such effects have been described for most neurotransmitter systems that may be affected by psychotherapeutic drugs, including serotonin (Emerit et al, 1992;Azmitia, 2001;Lesch, 2001;Nguyen et al, 2001;Okado et al, 2001;Rho and Storey, 2001), GABA (Levitt et al, 1997;Ikonomidou et al, 2001;Nguyen et al, 2001;Varju et al, 2001), dopamine (Levitt et al, 1997;Rho and Storey, 2001), norepinephrine (Duman and Alvaro, 1993;Rho and Storey, 2001), acetylcholine (Costa, 1993;Nguyen et al, 2001;Rho and Storey, 2001), and glutamate (McDonald and Johnston, 1990;Contestabile, 2000;Ikonomidou et al, 2001). The major classes of psychotherapeutic drugs target four neurotransmitter systems (dopamine, serotonin, norepinephrine, and GABA), and changes in various parameters of these systems have been reported in animals perinatally exposed to these drugs.…”

Multiple Serotonergic Brainstem Abnormalities in Sudden Infant Death Syndrome

“…We analyzed the 5-HT 1A receptor because it is found in high densities in regions in which binding was most severely reduced in previous studies, is recognized as a somatodendritic autoreceptor that controls 5-HT neuron firing, and plays important roles in cardiorespiratory control 12,[27][28][29][30] and neural development. 31, 32 We analyzed 5-HTT because it regulates synaptic 5-HT concentration 33 and because of the identification of SLC6A4 gene polymorphisms as risk factors for SIDS. [24][25][26] In addition, all SIDS cases and controls in this study were genotyped for the 5HTTLPR polymorphism to allow correlation of genotype with data on neuron count and binding density.…”