Perspectives on developmental neurobiology最新文献

Cholinergic afferents innervate cerebral cortex during the most dynamic period of neuronal differentiation and synapse formation, suggesting they play a possible regulatory role in these events. A number of in vivo studies have shown over the last decade that alterations in cholinergic innervation during early postnatal development can change various features of cortical ontogeny. In particular, neonatal lesions to basal forebrain cholinergic afferents result in delayed cortical neuronal development and permanently altered cortical cytoarchitecture and cognitive behaviors. Likewise, cholinergic manipulations affect morphological plasticity in cat visual cortex as well as in the somatosensory cortex of rodents. Furthermore, augmentation of cholinergic function by means of perinatal choline treatment enhances cognitive performance in a sex specific manner. Additional indications for a sexual dimorphism in cortical cholinergic innervation and resulting function are gathered from a variety of paradigms. Recent information about effects of NGF, BDNF and NTB-4/5 on cortical morphogenesis and plasticity reveals complex interactions between the cholinergic basal forebrain afferents and this neurotrophin family. Detailed studies on the expression of cholinergic receptor proteins in cortical development and their associated signal transduction pathways strongly point towards a morphogenetic function of muscarinic receptors, in particular. Transient receptor localization in thalamocortical terminal fields and on a variety of other non-cholinergic fiber bundles suggest a cholinergic role in target finding and/or synapse formation for cortical afferents and efferents. We propose a hypothesis regarding the mechanisms for cholinergic regulation of neuronal differentiation and synapse formation on the level of the individual growth cone and discuss possibilities for cholinergic interactions with differential gene expression. We conclude that understanding the precise role of the cholinergic system in cortical morphogenesis and its relationship to neurotrophin function will be of clinical relevance for a number of developmental brain disorders, including Down Syndrome and Rett Syndrome.

It is now well established that neurotransmitters act as growth-regulatory signals for neuronal and non-neuronal cells of both primitive and higher organisms, where they control cell proliferation, motility, survival, growth, differentiation, and gene expression. Many of these actions are reminiscent of the actions of other growth-regulatory signals such as growth factors, neurotrophins, and proto-oncogenes. How, then, do neurotransmitters exert these effects? Although some information is available concerning second messengers activated by these neurotransmitters in developing cells, little is known about subsequent steps involving signal transduction cascades leading to their final outcomes. This review attempts to provide testable hypotheses regarding possible cellular and molecular mechanisms downstream of second messengers activated by neurotransmitters, based on recent insights into signal transduction cascades activated by classical growth-regulatory signals. In many cases, there are clear points of convergence between these pathways, raising the interesting possibility that neurotransmitters and other growth-regulatory signals may cooperate to regulate developmental functions of cells and tissues.

A variety of studies support a trophic role for somatostatin in the developing nervous system, evidenced as stimulation of neurite outgrowth and axonal or neuronal migration in both in vivo and culture models. Cloning experiments have now demonstrated the existence of five subtypes of somatostatin receptor, differentially distributed in the nervous system, differentially linked to specific signal transduction systems and in certain cases differentially expressed during development. The combination of the differential and developmental regulation of expression of both the somatostatin peptides and their receptors thus provides great potential in terms of trophic effects. To substantiate trophic effects of somatostatin, data are presented from two different model systems, cultures of cerebellar granule cells as well as transgenic mice in which somatostatin is expressed under the control of the glial fibrillary acidic protein promoter. Finally, potential receptor subtypes and second messenger systems involved in these trophic effects are addressed.

Neurotransmitters and their receptors appear early during nervous system development and are thought to play important roles in neurite outgrowth, growth cone motility, target cell selection and synaptogenesis. In vivo studies in both vertebrates and invertebrates have shown that the perturbations of embryonic transmitter expression result in abnormal morphological and synaptic development. In vitro studies have further revealed that transmitters are capable of affecting neurite outgrowth and growth cone behaviour. The precise cellular mechanisms by which neurotransmitters affect these developmental steps are, however, poorly defined. In vitro, a presynaptic neuron from the mollusc Lymnaea stagnalis releases dopamine, which induces both growth cone attraction and growth cone collapse of target and non-target cell growth cones, respectively. We propose that the ability of dopamine to differentially affect growth cone motility of two cell types results from a divergence of the dopamine receptor-activated second messenger pathways at the G-protein level. Such transmitter-receptor interactions between growth cones of specific neurons may not only induce changes in the growth cone motility, but may subsequently play an important role in target cell selection and specificity of synaptogenesis.

Gamma-aminobutyric acid (GABA) is one of the principle inhibitory neurotransmitters in the mature spinal cord. It effectively suppresses synaptic transmission by mechanisms of postsynaptic and presynaptic inhibition. The function of GABA is less well understood early in spinal cord development, when the amino acid is transiently expressed in most neurons, and it depolarizes instead of hyperpolarizes neurons. This article reviews the possible physiological roles of GABA in modulating synaptic transmission, promoting neuronal development, and regulating neuronal pH during early stages of spinal cord differentiation. It is proposed that despite its depolarizing action, GABA acts as an inhibitory neurotransmitter that may also function as a neurotrophic agent.

Distinct GABAA-receptor subtypes, differing in subunit composition, physiology, and pharmacology, are expressed in fetal, neonatal, and adult brain. Their developmental schedule, evidenced by the differential maturation of the GABAA-receptor subunits alpha 1, alpha 2, and alpha 5, is similar in rodents and primates, indicating that the regulation of receptor subtypes is conserved across species. "Adult" GABAA-receptors, characterized by the alpha 1-subunit immunoreactivity, are largely absent from fetal brain. They appear, however, before the onset of functional inhibitory connections, suggesting that GABAA-receptors may play an active role in the formation of GABAergic synapses. In neocortex, the maturation of GABAA-receptor subtypes is governed by an intrinsic program, leading to an area- and lamina-specific distribution as early as E20 in rats. In primary somatosensory and visual areas, this pattern is influenced postnatally by the ingrowing thalamocortical projection, a process that can be prevented experimentally by lesioning the thalamus at birth. Altogether, the expression of GABAA-receptor subtypes in developing brain reflects the changing functional needs of neurons during differentiation, the formation of inhibitory circuits, and the emergence of functionally distinct brain compartments.

Neurite outgrowth and growth cone motility are among the many aspects of neuronal development that can be affected by specific neurotransmitters. This was first demonstrated in experiments on identified molluscan neurons that were isolated from mature ganglia and cultured under conditions that promote the regeneration of new neurites. The application of serotonin to a regenerating Helisoma neuron B19 produced an abrupt, reversible cessation of neurite outgrowth and growth cone motility. While this type of response would subsequently be demonstrated for other neurons and neurotransmitters in many different invertebrate and vertebrate species, experiments on Helisoma neurons have continued to play a pivotal role in advancing this field. In this paper, the mechanisms and sites of serotonin action and how these responses are manifested in vivo during embryonic development are discussed. Experiments primarily on neuron B19 have shown that serotonin acts on a novel serotonin receptor that is coupled to the elevation of cyclic AMP. This intracellular messenger directly activates a class of cyclic-nucleotide-gated sodium channels, leading to sodium influx, membrane depolarization, and activation of voltage-gated calcium channels. The resulting elevation of intracellular calcium acts through a calcium/calmodulin-dependent pathway to inhibit neurite outgrowth and growth cone motility. Although the final steps have yet to be completely resolved, they undoubtedly involve calcium-dependent regulation of cytoskeletal components. Regarding the sites of serotonin action, serotonin responses have been localized to growth cones and even filopodia in specific neurons. However, some studies suggest that neurite development may actually be regulated by serotonin in a paracrine, non-localized manner in a surprisingly large percentage of Helisoma neurons. Finally, experiments on Helisoma embryos have investigated how serotonin actually regulates the in vivo development of specific neurons. Pharmacological treatments that reduce the serotonin concentration in embryos affected the neurite morphology and synaptic efficacy of neuron B19 and the amount of neurite branching in embryonic neuron C1. All of these responses were consistent with the primary action of serotonin being the inhibition of neurite outgrowth, as predicted by the original cell culture studies.

During development of the nervous system a common set of signal transduction pathways appear to regulate growth cone behaviors, synaptogenesis and natural cell death, three fundamental processes that comprise the "neurodevelopmental triad". Among the intercellular signals that coordinate the developmental triad in the mammalian brain are glutamate (the major excitatory neurotransmitter) and beta-amyloid precursor protein (beta APP). Localization of ionotropic glutamate receptors to dendritic compartments allows for selective regulation of dendrite growth cones and spine formation by glutamate released from axonal growth cones and presynaptic terminals. Expression of particular subtypes of glutamate receptors peaks during a developmental time window within which synaptogenesis and natural neuronal death occur. Calcium is the preeminent second messenger mediating both acute (rapid remodelling of the microtubule and actin cytoskeletal systems) and delayed (transcriptional regulation of growth-related proteins; e.g., neurotrophins) actions of glutamate. The expression of beta APP in brain is developmentally regulated and it is expressed ubiquitously in differentiated neurons. beta APP is axonally transported and secreted forms of beta APP (sAPPs) are released from neurons in an activity-driven manner. Secreted APPs modulate neuronal excitability, counteract effects of glutamate on growth cone behaviors, and increase synaptic complexity. Acute actions of sAPPs appear to be transduced by cyclic GMP which promotes activation of K+ channels and reduces [Ca2+]i. Delayed actions of sAPPs may involve regulation of gene expression by the transcription factor NF kappa B. Finally, the striking effects of glutamate, neurotrophic factors, and sAPPs on synaptogenesis and neuronal survival in cell culture systems and in vivo suggest that each of these signals plays major roles in the process of natural cell death. The same signalling mechanisms that mediate adapative regulation of neuroarchitecture during brain development appear to play prominent roles in maladaptive neurodegenerative processes in an array of disorders ranging from stroke to epilepsy to Alzheimer's disease.

GABA exerts a variety of trophic influences on developing brain cells, as reviewed in this issue. During early stages of brain development, GABAergic axons course through regions where other neurotransmitter phenotypes are being generated. This raises the question of whether GABA may influence the ontogeny of these neurotransmitter systems in the embryonic brain. The brainstem provides a good example of this relationship, since GABAergic axons pass through the anlage of the developing raphe nuclei when serotonergic (5-HT) neurons are just beginning to differentiate and migrate away from the ventricular zone. Evidence that GABA regulates development of these and adjacent noradrenergic neurons has recently been obtained using embryonic brainstem cultures, which contain differentiating 5-HT, tyrosine hydroxylase (TH), and GABA neurons. These cultures also express multiple GABAA-receptor subunits that form functional GABAA/Cl- channels. GABAA receptor ligands produce differential effects on survival and growth of monoamine (5-HT, TH) and GABA neurons, and on expression of GABAA subunits in these cultures. These findings provide evidence that GABA can selectively regulate development of neurons of different neurotransmitter phenotypes, as well as developmental expression of its own receptors, and suggest that in utero exposure to GABAA receptor ligands could produce imbalances in monoaminergic versus GABAergic neurotransmission in the developing brain. Dieldrin, an organochlorine pesticide that acts as a GABAA antagonist, has potent effects on survival, and neurite outgrowth by 5-HT neurons, and GABAA subunit expression in brainstem cultures. Thus, maternal exposure to organochlorine pesticides could pose a risk to fetal brain development, especially during the first trimester of pregnancy.

GABA is present in organisms belonging to at least four of the five kingdoms. It acts as a neurotransmitter, a paracrine signaling molecule, a metabolic intermediate, or a trophic factor. In mammals, GABA synthesis depends on two forms of the enzyme glutamic acid decarboxylase--GAD65 and GAD67--that may serve distinctive functions within GABA-producing cells. The two GADs derive from two genes, which are differentially regulated, though nearly every GABA-producing cell contains both forms of GAD. GAD67 predominates early in development and after neuronal injury, consistent with a possible role in producing GABA for trophic use. In the embryo, GAD67 transcripts also undergo alternative splicing, which gives rise to truncated forms. In the mature neuron, GAD67 is present in both terminals and the cell body, where it may subserve a nonsynaptic, intracellular GABA pool. In contrast, GAD65 is usually expressed later in development and is primarily localized to nerve terminals. GAD65 enzymatic activity is more subject to regulation by cofactor binding and neuronal activity, consistent with its involvement in the production of synaptic GABA. Thus, while both GAD67 and GAD65 mediate the synthesis of GABA, their unique distributions and expression patterns suggest divergent functional roles.