Perspectives on developmental neurobiology最新文献

Little is known about the transmitter choice of neurons in the central nervous system. Recent evidence suggests that precursor cells in the mammalian neocortex are multipotential and generate GABAergic as well as glutamatergic neurons. Environmental interactions within the proliferative zone seem to specify the transmitter phenotype of the neurons generated by the multipotential precursor cells. Precursor cells are restricted in the ventricular zone of a given region in the forebrain and do not intermingle with precursor cells from the adjacent regions. They are thus exposed to distinct region-specific environmental influences that instruct the different neuronal phenotypes found in different regions of the adult brain. Amongst the factors that influence the transmitter choice of early neuroblasts are transmitters themselves. Activity-dependent mechanisms mediated by a variety of neurotransmitters and their receptors could be the key players in specifying neuronal phenotypes at early developmental stages in the ventricular zone.

Cerebellar granule cells isolated from postnatal day 7 rat pups are ideal for studying epigenetic events associated with the regulation of neuronal gene expression. These cultures contain from 90 to 95% glutamatergic granule cells and express mRNAs encoding a variety of ionotropic and metabotropic glutamate receptors as well as virtually all of the GABAA-receptor subunit mRNAs to different extents. A unique feature of this culture system is that the neurons undergo time-dependent maturation changes in vitro that mimic many of the characteristics of these receptors occurring in vivo. Granule cell cultures in vitro require depolarizing concentrations of KCl for long-term growth and survival. Both N-methyl-D-aspartate (NMDA) and GABA have been reported to exert trophic actions on these cells replacing the requirement for maintaining the cultures in high KCl. Cerebellar granule cells maintained under different conditions in vitro can be induced to alter their patterns of maturation, as indicated by the different temporal changes in gene expression of receptor subunit mRNAs and proteins. The focus of the current studies is the effect of NMDA afferent synaptic signaling on the changes in mRNA content and functional properties of GABAA receptors and how this may relate to comparable changes shown to occur in vivo.

Current data on the role of classical neurotransmitters as multiple and multifunctional regulators of early embryogenesis are reviewed. It is shown that these developmental regulators are coupled with second messengers. Peculiarities of this prenervous coupling emphasized and are used as the basis for discussing the problem of the evolutionary origin of cell regulatory systems.

It is well recognized that the neurotrophin family of factors as well as neurotransmitters play critical roles in the ontogeny of the brain. Moreover, a growing literature suggests that these environmental signals do not operate individually, but interact in critical ways to enhance maturation. This review focuses on three brain systems where this collaboration is particularly evident: the cerebellum, the basal forebrain-hippocampus and locus coeruleus-hippocampus. The material presented indicates that cross-talk between neurotransmitters and neurotrophins may be a mechanism common to the development of multiple neuronal groups throughout the central nervous system. Moreover, this cross-talk appears to involve the interaction of both neuronal and glial cell populations.

Recent studies have demonstrated that many of the mRNAs encoding GABAA-receptor subunits in the cerebellum exhibit distinct temporal profiles of expression. The levels of six of these subunit transcripts increase severalfold in the second week of postnatal ontogeny. Findings from a variety of experimental systems suggest that the onset and increases in subunit mRNA expression are mediated by the interaction of genetic and epigenetic programs. The initiation of subunit mRNA expression occurs relatively early in cellular maturation and may be directed by intrinsic mechanisms. However, the levels of expression attained in adult animals may be controlled by extrinsic signals received by neurons during the postnatal maturation process.

If GABA is serving a trophic role during early brain development, before taking on its function as a neurotransmitter, interference with the function of GABA during this period should have a profound influence on neural organization. We have addressed this hypothesis by evaluating the effects of exposing rat fetuses to diazepam (DZ), a positive modulator of GABA at the GABAA receptor, over gestation days 14 to 20. Studies have shown that adult rats exposed in utero to DZ over this developmental period make inappropriate behavioral responses and have altered neural and hormonal responses to environmental stimuli that threaten the organism's stability and homeostasis. Thus, the early exposure led to altered adaptive responses. These effects of the early exposure did not become apparent until late in adolescent development. Furthermore, specific behavioral and neural responses to environmental challenges normally emerge over adolescent development. Other studies have shown that the GABAA receptor in adult brains is responsive to environmental challenges. Thus, we hypothesize that early modulation of the action of GABA mediated via the GABAA receptor interfered with the neural organization of adaptive responses.

GABA is present in certain retinal neurons before synapses are formed, and it has a variety of effects on the developing retina. Its exact role in retinal maturation is not clear; however, there is growing evidence from rabbit retina that neonatal horizontal cells produce GABA within the outer retina, which in turn is necessary for normal synapse formation of photoreceptors. In addition to its classic role as an inhibitory transmitter, GABA in the neonate increases intracellular calcium levels in selected cells. This latter property is lost during postnatal development, along with a general decrease in the level of expression of both pre- and postsynaptic GABAergic markers and a decrease in the number of GABAergic neurons. The adult GABAergic circuitry in adult retina may represent a restricted, perhaps simplified version of the more complex and diversified interactions of the GABA system during development.

Gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the mature vertebrate retina, where it is localized predominantly in amacrine cells, and to a lesser extent in other cell types. During development, GABA is expressed transiently in additional cells, including retinal ganglion cells and horizontal cells. Elements of the GABA system, including GABA uptake and release mechanisms and GABA receptors, are also expressed early in retinal development, well in advance of the onset of visual function. The GABA transporter is a major component of the GABA system in the mature retina, and is most likely responsible for GABA release early in development, prior to the establishment of vesicular synaptic transmission. GABA, produced by amacrine cells and retinal ganglion cells, may serve a developmental role in the establishment of circuitry in the retinal inner plexiform layer and may also be involved in the formation of appropriate central connections by retinal ganglion cell axons.

Early and ubiquitous detection of GABA in the rat spinal cord before the occurrence of synaptogenesis has led to the concept of a neurotrophic role of GABA, in addition to a promoting effect on neurite extension and neurodevelopment. The aim of this study was to further establish, in vivo, evidence for a link between the maturation of spinal cord innervation and the regulation of several isoforms of the synthetic enzymes of GABA, the glutamic acid decarboxylases GAD65, GAD67, and EP10, the embryonic truncated form of GAD67. Neonatal capsaicin treatment was used to induce a specific loss of afferent fibers (unmyelinated C fibers, thin myelinated fibers A delta) to the dorsal horn. The regulation of various GAD mRNAs was investigated using sensitive techniques such as RT-PCR and in situ hybridization. The sensitivity of the methods was further enhanced by the use of a gaseous detector (beta-imager) to quantitate the mRNAs species. After neonatal capsaicin treatment, higher levels of GAD67 mRNA were detected transiently during the postnatal development of the rat spinal cord. A maximum two-fold increase of GAD67 mRNA was found on the day following the capsaicin injection and reached control values within 3 weeks. In contrast, GAD65 mRNA levels remained low and were unaffected by the treatment, and EP10 was not detected. In addition, we have found a similar upregulation, with the same time course, of the cytoskeletal protein beta-actin. The capsaicin-induction of mRNA synthesis was, however, two-fold greater for beta-actin than for GAD67. Moreover, since this upregulation of GAD67 mRNA coincides with the sprouting of unaffected afferent fibers and of 5HT axons, one can hypothesize that GAD67 participates in the structural plasticity occurring in reaction to the capsaicin-induced partial deafferentation.

The roles of GABA during development, as either a putative neurotransmitter or a nonsynaptic trophic factor, are being discussed intensely in recent literature. We offer an anatomical framework to better understand these possible roles in the developing cerebral cortex. During the early development of the cerebral cortex, GABA-containing cells constitute an outstanding cell population in the primordial plexiform layer, but they later distribute into at least four compartments. These include (1) Cajal-Retzius cells in layer I and (2) the subplate cells. Certain of these GABA-containing cell groups may disappear either by ceasing their expression of GABA, dilution in a growing brain volume, or cell death, possibilities that are reviewed here. The chemical tags that characterize Cajal-Retzius cells, both in the forming isocortex and Ammon's horn, are discussed. Another cell population that also belongs to the primordial plexiform layer is formed by (3) the tangentially migrating cells of the deep intermediate layer. These migrate away from the isocortical primordium to invade, and contribute cells to, the forming stratum oriens of the Ammon's horn. Since these cells cross cortical area boundaries, their tangential migration is relevant to the issue of cortical area specification during development. Finally, GABA-immunoreactive cells in the developing cortical plate are considered to be (4) the future GABAergic interneurons. A hypothetical mechanism is presented here to explain their acquisition of laminar positions, which is known to take place simultaneously, and with an identical "inside-out gradient," to the pyramidal cells generated contemporarily.