Mounting evidence suggests that cognitive impairment begins with subtle alterations of synaptic efficacy prior to frank neuronal degeneration, and synaptic dysfunction may be induced by diffusible oligomeric assemblies of amyloid beta peptide (Aβ). The mechanisms underlying Aβ neurotoxicity are complex but might involve N-methyl-D-aspartate receptor (NMDAR). This review focuses on the action of NMDAR and its subunits in Aβ-induced synaptic dysfunction. The localized apoptotic mechanism that contributes to synaptic dysfunction in Alzheimer’s disease will also be discussed.
The objective was to study neuronal apoptosis and changes in the proteins related to the mitochondrial pathway in the hippocampus of a rat model of Alzheimer’s disease (AD) and discuss its significance in AD. Thirty-six Sprague-Dawley rats were divided into 3 groups: a normal group, a control group and an AD group. AD was established by injecting β-amyloid1–42 (Aβ1–42) into the hippocampus. Learning and memory ability was estimated with a Y maze at different times. The apoptotic neurons were detected by the TdT-mediated X-dUTP nick end labeling (TUNEL) method. Cytochrome C and caspase-9 protein expression in the hippocampus was detected by Western blot. The results showed that there was obvious impairment of learning and memory in rats of the AD group after Aβ1–42 injection. The apoptotic neurons in the hippocampus of the rats in the AD group were significantly increased compared with the normal group and the control group (p < 0.01), and the expression of cytochrome C and caspase-9 in hippocampus in AD group was significantly increased too (p < 0.01). The results suggest that the mitochondrial pathway is one of the important neuronic apoptotic pathways induced by Aβ1–42 in the hippocampus, and may play an important role in the pathogenesis of AD.
The expression patterns of the two subunits of the metabotropic GABAB receptor, GABABR1 and GABABR2, vary among various neural regions and their relative expression in the rat central vestibular system remains unknown. To identify the expression patterns of these two subunits of the metabotropic GABAB receptor in the vestibular nucleus of adult rats, double immunofluorescence experiments were performed. GABABR1 or GABABR2 immunoreactivity was observed in neurons and neuropilar elements of the vestibular nuclear complex and its subgroups x and y. These neurons were oval, multipolar, fusiform or triangular in shape. In contrast to other brain regions, individual neurons or neuropil within the various vestibular subnuclei and subgroups displayed comparable levels of GABABR1 and GABABR2 immunoreactivity. Double immunofluorescence experiments further demonstrated the coexpression of GABABR1 and GABABR2 receptor subunits in individual central vestibular neurons. The present findings provide histological evidence of the heterodimeric nature of GABAB receptors that mediate inhibitory neurotransmission in the rat vestibular nuclei.
Silver impregnation studies of neurons in the developing human nervous system had attracted only a fair amount of studies due to the difficulty of the technique. This report is concerned with studying the morphogenesis of pyramidal and stellate cells during development in different regions of the cortex. No silver-impregnated cells were present before 21 weeks of gestation in most cortices except for the frontal cortex. Between 21 and 25 weeks, pyramidal cells were clearly demonstrated. By 27 weeks of gestation and thereafter, secondary branching was observed in these cells. Two types of stellate cells were identified at week 30 and thereafter. A difference in the degree of differentiation was also recorded between different cortical regions during development.
The development of several new magnetic resonance imaging (MRI) techniques has facilitated serial observations of the developing human brain in utero. For example, the noninvasive technique of functional MRI, which is used to study brain anatomy, function and metabolism in both humans and animals, has already enhanced our understanding of brain development and behavior relations. Currently, three main kinds of functional MRI techniques are used to study the developing brain: blood oxygenation level-dependent imaging, diffusion tensor imaging and magnetic resonance spectroscopy. When used in developmental research, these techniques can detect variations and injury, which conventional MRI cannot. Thus, they offer far greater opportunities to explore the relationships between structure and function, and to interpret developmental mechanisms, as well as to detect malformations and pathologies at the cognitive, emotional and behavioral level. These methodologies and their application to brain development are reviewed in this paper.
Structural magnetic resonance imaging has gained widespread attention over the last decade, especially following the advances in automated image processing algorithms. It is an interesting approach that, among other applications, allows investigating and describing normal and disturbed human brain development. With this overview, we aim to point out special aspects that may arise when imaging children, with regard to study design, data acquisition and data processing. We conclude with shortly addressing the potential insights to be gained from such studies.
Background: Dab2, 1 of the 2 mammalian orthologs of the Disabled protein in Drosophila, is a mitogen-responsive phosphoprotein and a cytoplasmic adaptor involved in several signal transduction pathways. Deficiency in Dab2 affects endodermal cell positioning and is embryonically lethal. Aims and Results: In the present study, the Dab2 expression pattern in mouse embryos from embryonic day (E)7.5 to E9.5 was first determined by specific immunohistochemical staining. Dab2 protein was expressed exclusively in the extraembryonic endoderm at E7.5 and was detected within the cranial mesenchyme, heart and foregut epithelium at E8.5. By E9.5, the protein was also localized in the roof plate of the hindbrain neural tube and within the branchial arch mesenchyme and epithelium. Next, to help define the role of Dab2 protein in early embryonic development, antisense oligodeoxynucleotides (ODNs) were microinjected into mouse embryos to inhibit Dab2 expression. The protein expression within the neural tube and cranial mesenchyme was greatly reduced following microinjection at E8.5 and culturing embryos intact with a whole-embryo culture system for 8 h in vitro. Moreover, 26.7% of the injected embryos exhibited a twisted neural tube or an unturned body axis. Twenty-four hours following microinjection of antisense ODNs, 70% of the injected embryos showed structural abnormalities mainly affecting the body axis, otic placode, forelimb buds, branchial arches and neural tube. Excessive cell death was detected histologically in the ventral part of the neural tube, although the expression of Dab2 protein had resumed by this stage (24 h following microinjection). Conclusion: We conclude that Dab2 plays an important role in mouse embryonic development between E8.5 and E9.5, as a reduction in Dab2 expression during this period was found to disturb normal development.
This paper summarizes the various methodologies used in magnetic resonance imaging (MRI) and presents the background logic behind these methodologies. The usage of MRI in the study of human subjects and animals is discussed and highlighted. Select examples of animal MR images are presented.
The human brain undergoes changes in morphology, volume, composition and function during brain maturation. Of the various available medical imaging investigations, ultrasound and MRI are most commonly used for assessing the developing brain. Being radiation-free and non-invasive, both imaging modalities allow in vivo serial examinations of the brain during maturation without health risks. In addition, MRI has the benefit of demonstrating certain functional aspects of the brain aside from examining morphology, further adding to the knowledge of brain development. This paper reviews the current main imaging investigations used for assessing the developing human brain, from the fetal stages to childhood.
Hirschsprung’s disease, or congenital megacolon, is the most common gastrointestinal motility disorder in newborns. The prominent feature of Hirschsprung’s disease is an abnormal dilatation of the distal colon resulting from a regional absence or reduction of enteric ganglion cells. It has been known that all intrinsic enteric ganglion cells are derived from neural crest cells, which migrate along defined pathways from the neural tube (embryonic central nervous system) to the gut during embryonic development. Recent studies on avian embryos have also indicated that neural crest cells at the sacral level contribute a significant number of enteric neurons to the hindgut, the region of the gut where aganglionosis is usually detected in Hirschsprung’s disease. In the present study, we aimed to identify anomalies in the early migration of sacral neural crest cells in the Dominant megacolon(Dom) mouse mutant, a model for Hirschsprung’s disease. A combination of whole embryo culture, in situ cell labeling and histochemical staining was used to follow the early sacral neural crest cell migration. In the wild-type embryos, when sacral neural crest cells caudal to the 24th somite were labeled at embryonic day 10.0 (E10.0), labeled cells were found in the mesenchyme on the two sides of neural tube and many of them resided in the region of dorsal root ganglia at E11.0. Some of them were also found in the region around the dorsal aorta. In embryos heterozygous and homozygous for Dom, similar distribution and migratory pattern were found, indicating that the early migration of sacral neural crest cells was not affected in the mutant. Our results hence implicated that anomalies in the early sacral crest cell migration are unlikely to be a cause of aganglionosis in the hindgut of the Dom mutant.
Using MRI, the ratios of the anterior posterior (AP) lengths of the eyes versus the AP lengths of the corneae to the external occipital protuberances were found to decrease from 28 weeks of gestation onwards, while the ratios of the transverse diameters of the eyes versus the transverse diameters of the zygomatic bone to the nasal cavity increased till term. No further change in the ratios of the AP or transverse diameters was observed even till three years of age.
γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the neostriatum. Functions of GABA are mediated by GABAA and GABAB receptors in the neostriatum. In order to investigate the developmental expression of GABA receptor subunits (GABAAα1, GABAAα3 and GABAAα6; GABAAβ2 and GABAAβ3, and GABABR1 and GABABR2) in the rat neostriatum, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence were performed. Tissues were obtained from rats on postnatal day (PND) 1, PND 7 and PND 14, and from adult rats. RT-PCR indicated that GABAAα1 and GABAAα6 mRNA levels were low, but that GABAAβ2 and GABAAβ3 mRNAs levels were high during the early postnatal period. Immunofluorescence revealed that GABAAα1 immunoreactivity was only observed in striatal interneurons in PND 14 and in adult rats. Immunoreactivity for GABAAα6 was only observed in PND 14 and adult animals. GABABR1 immunoreactivity was found to be expressed by perikarya of striatal neurons at all ages examined. In contrast, GABABR2 immunoreactivity was mainly observed in choline acetyltransferase-positive striatal interneurons in PND 14 and adult rats. The present results indicate that there are differential patterns of developmental expression of GABA receptor subunits in the neostriatum, with important implications for the development of GABA systems in rat basal ganglia.
To investigate the variation in retinal circulation in patients with different degrees of myopia and different age by fluorescence fundus angiography (FFA). Thirty myopic patients (60 eyes), 20–54 years of age, with various degrees of myopia were evaluated. All patients underwent fundus photography and FFA using a standard technique. Patients with other ophthalmologic diseases possibly affecting the retrobulbar circulation and those with a history of laser treatment or intraocular surgery were excluded. Vascular filling patterns at arterial phase, arterial-venous phase and venous phase were reviewed. The average filling times at each phase were significantly delayed in severe myopia, but there was no difference between eyes with mild and medium myopia. There was no statistically significant correlation between mean filling time and age. The findings indicated a significant correlation between the intraocular blood circulation and the degree of myopia.
Magnetic resonance imaging (MRI) of the fetal brain is a useful adjunct to prenatal sonography, providing a more complete evaluation of fetal brain abnormalities to aid and influence clinical decision-making during pregnancy. This article will review the uses and techniques of fetal MRI, discuss the normal appearance of the fetal brain on MRI, and outline clinical applications of fetal MR imaging.
Myelomeningocele (MMC), one of the most common congenital malformations, can result in severe lifelong disabilities, including paraplegia, hydrocephalus, Arnold-Chiari II malformation, incontinence, sexual dysfunction, skeletal deformations, and mental impairment. MMC was the first nonlethal anomaly to be treated by fetal surgery. Studies in animals provide compelling evidence that the primary cause of the neurological deficit associated with MMC is not simply incomplete neurulation but rather chronic mechanical injury and amniotic-fluid-induced chemical trauma that progressively damage the exposed neural tissue during gestation. Initial results suggest that the surgical repair of MMC before 25 weeks of gestation may preserve neurological function, reverse the hindbrain herniation of the Arnold-Chiari II malformation, and obviate the need for postnatal placement of a ventriculoperitoneal shunt. As it is currently unknown whether fetal surgery for MMC is truly beneficial compared to standard postnatal care, a randomized, controlled clinical trial has been initiated within the United States.
Two lectins, Griffonia simplicifolia I isolectin B4 (GS-I lectin) and Lycopersicon esculentum (LE) lectin, reported to be specific microglia markers in a number of animals including rodents, were used to stain hamster retinas. In the adult hamster retina, both of them failed to stain microglia but instead labeled astrocytes (in addition to endothelial cells). GS-I lectin-positive astrocytes were mainly located at peripheral regions of the retina but were variable in number and staining intensity, while LE lectin stained most astrocytes as judged by co-localization with anti-glial fibrillary acidic protein staining. To see whether astrocytes (and/or microglia) would be labeled by the lectins during postnatal retinal development, retinas from newborns all the way to adults were studied. Starting from P0, GS-I lectin selectively labeled astrocytes located adjacent to and peripheral to the tips of developing blood vessels, suggesting a functional association of glycoproteins containing α-D-galactose (the terminal sugar residue with binding affinity to GS-I) with the migration of the astrocytic front during development. The GS-I lectin staining on this population of astrocytes became reduced as the astrocytic front reached the retinal periphery, so that in the adult only astrocytes in the periphery became positive for GS-I. In contrast, LE lectin stained most astrocytes in the developing retina, starting from P2 and with maximum staining intensity achieved around P14, which continued unchanged to adulthood. During early postnatal retinal development, both lectins could label microglia, but the staining was abolished well before the retina became mature. GS-I could label microglia until P18, and the stained cells were mainly confined to the retinal periphery where blood vessels were absent, suggesting that expression of the terminal α-D-galactose residue is regulated by interaction with the developing vasculature (and/or astrocytes). LE could mark microglia till P6, but the labeling was weaker compared with GS-I. The results indicate that at least in the hamster, GS-I and LE lectin may be a more selective marker for retinal astrocytes than microglia. It would be interesting to see whether some other animals will exhibit a similar picture, and whether the expression of the sugar residues (specific for GS-I and LE lectin binding) on astrocytes instead of microglia will confer any functional consequences uniquely different from those animals with specific microglia binding.
