In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and ...age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was seen throughout superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum in postmortem brains from ASD patients but not control brains. We found significant increases in both nestin and CD34, which are markers of angiogenesis localized to pericyte cells and endothelial cells, respectively. This labeling profile is indicative of splitting (intussusceptive), rather than sprouting, angiogenesis indicating the blood vessels are in constant flux rather than continually expanding.
The hypothesis explored in this review is that the high levels of serotonin in the blood seen in some autistic children (the so‐called hyperserotonemia of autism) may lead to some of the behavioral ...and cellular changes also observed in the disorder. At early stages of development, when the blood–brain Barrier is not yet fully formed, the high levels of serotonin in the blood can enter the brain of a developing fetus and cause loss of serotonin terminals through a known negative feedback function of serotonin during development. The loss of serotonin innervation persists throughout subsequent development and the symptoms of autism appear. A review of the basic scientific literature on prenatal treatments affecting serotonin is given, in support of this hypothesis, with an emphasis on studies using the serotonin agonist, 5‐methoxytryptamine (5‐MT).
In work using 5‐MT to mimic hyperserotonemia, Sprague‐Dawley rats are treated from gestational day 12 until postnatal 20. In published reports, these animals have been found to have a significant loss of serotonin terminals, decreased metabolic activity in cortex, changes in columnar development in cortex, changes in serotonin receptors, and “autistic‐like” behaviors. In preliminary cellular findings given in this review, the animals have also been found to have cellular changes in two relevant brain regions: 1. Central nucleus of the amygdala, a brain region involved in fear‐responding, where an increase in calcitonin gene related peptide (CGRP) was found 2. Paraventricular nucleus of the hypothalamus, a brain region involved in social memory and bonding, where a decrease in oxytocin was found. Both of these cellular changes could result from loss of serotonin innervation, possibly due to loss of terminal outgrowth from the same cells of the raphe nuclei. Thus, increased serotonergic activity during development could damage neurocircuitry involved in emotional responding to social stressors and may have relevance to the symptoms of autism.
Serotonin is known to play a role in brain development prior to the time it assumes its role as a neurotransmitter in the mature brain. Serotonin regulates both the development of serotonergic ...neurons (termed autoregulation of development) and the development of target tissues. In both cases, the astroglial-derived protein, S-100β plays a role. Disruption of serotonergic development can leave permanent alterations in brain function and behavior. This may be the case in such human developmental illnesses as autism and Down Syndrome.
Activation of 5HT1A receptors produces many different physiologic responses, which may be due to their localization on diverse cells in the brain. A 5-HT1A receptor antipeptide (aa170–186) antibody ...was produced that showed both high titer for peptide binding and immunocytochemical staining. Studies performed in perfusion-fixed brain tissue showed immunoreactive neurons, glial, and ependymal cells in the rat, mouse, cat, and monkey. Results from our studies of Macaca fascicularis brains are presented. We observed two main neuronal labeling patterns in the primate brain: (1) A general, diffuse somatodendritic distribution of 5-HT1A receptor immunoreactivity is seen in the raphe nuclei where the dendritic shaft, its branches and spines, and the entire perikaryon are immunolabeled. This pattern is also observed in the nucleus locus coeruleus, in scattered large brainstem reticular neurons, and in dentate gyrus hilar interneurons. (2) A discrete localization of 5-HT1A receptor immunoreactivity on the initial axon segment (axon hillock) is noted in pyramidal neurons of layer III and V of cerebral cortex, Cornu Ammonus (1–4) of the hippocampus, and in most brainstem and cervical spinal cord motoneurons. In addition to neuronal labeling, 5-HT1A receptor immunoreactivity is seen in the cell body and processes of astrocytes, and other nonneuronal cells. This pattern is particularly evident in the white matter of cerebral cortex and spinal cord, the pontine nuclei, the brainstem tectum, and the hilus of the dentate gyrus. The clinical implications of 5-HT1A cellular localization are briefly discussed.
Learning and memory are often correlated with cellular changes within the hippocampus, and drugs or environmental factors which affect learning and memory will thus often induce observable ...morphological changes in this structure. Like tetrahydrocannabinol (THC) itself, many synthetic cannabinoids such as the CB-1 receptor agonist WIN 55,212-2 will induce learning and memory changes. In the current study, we investigate whether or not these changes could be related to structural changes within the hippocampus. Adult male Sprague–Dawley rats were injected twice daily (12:00 and 0:00 h) subcutaneously with WIN 55,212-2 (2.0 mg/kg) in DMSO or DMSO for 21 days. On day 22, animals were perfused and stained immunochemically for the dendritic marker MAP-2, or with cresyl violet. Morphometric analysis showed dendritic rearrangement with increased staining of MAP-2 in CA3 and the lower blade of the dentate gyrus. However, a loss of staining was observed in CA1. Counting of cresyl violet stained sections showed an apparent increase in granule cell number in the lower blade of the dentate gyrus. This work shows the potential for cannabinoids to influence hippocampal morphology. The pattern of changes may be similar to that seen after ischemic or toxic damage, but may be opposite to changes seen in stress.
S-100
β is a neurotrophic factor released by astroglial cells and localized to chromosome 21, within the region which is considered obligate for Down's syndrome (DS). S-100
β is increased in the ...postmortem brains of both DS and Alzheimer's disease. Transgenic mice, produced by insertion of the human gene for S-100
β, were examined for dendritic development at two ages, using an antibody against microtubule associated protein-2 (MAP-2). At the earliest stages, the density of dendrites within the hippocampus of transgenic animals exceeded that of controls. Also, MAP-2 immunostaining was evident in the region of the cell body. By 1 year of age, the transgenic animals had significant loss of dendrites compared to controls and the number of cells showing cell body staining was further increased. These pathological changes could be indicative of the presence of neurofibrillary tangles and cytoskeletal collapse. Behaviorally, younger transgenic animals could not perform in a learning task as well as controls. Together, these findings suggest that increased S-100
β in brain may lead to accelerated development, followed by increased aging. The pathological changes may prove useful as an animal model of Down's syndrome and Alzheimer's disease.
Isolation-rearing of rats causes a variety of behavioral changes, including anxiety, learning deficits and sensory changes related to schizophrenia. Similar changes are seen following loss of ...serotonin during development. Thus, the effects of isolation-rearing on behavior may be due to changes in serotonin.
Sprague-Dawley rats were raised in groups of four (social animals) or in isolation, from postnatal day 22 until postnatal day 64. The hippocampi were examined immunochemically for changes in serotonin. Our findings show that serotonin terminals are lost throughout the CA regions of hippocampus, where there is also an associated loss of dendrites, but not in the molecular layer of the dentate gyrus. Thus, some of the brain and behavioral changes seen in isolation-reared animals could be due to loss of serotonin.
Abstract Prior research has reliably found high blood (hyperserotonemia) – but low brain – serotonin levels in autistic individuals. At early stages of development, high levels of serotonin in the ...blood may enter the brain of a developing fetus, causing a loss of serotonin terminals through negative feedback and thus disrupting subsequent serotonergic function. The current study extends earlier findings in a developmental hyperserotonemia (DHS) model of autism in Sprague–Dawley rats by treating 8 dams of developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational day 12 to post-natal day 20; PND 20). DHS pups exhibited post-injection seizures, which were non-existent in saline-treated pups ( p < 0.05). Behavioral results in infancy indicated that DHS pups spent less time with the dam during the active phase on PNDs 15–17 ( p < 0.05) and experienced decreased maternal bonding in a return to dam task on PND 17 ( p < 0.05). On subsequent tests, DHS animals exhibited greater gnawing reactions to a novel stimulus ( p < 0.05), less behavioral inhibition ( p < 0.05), and had fewer olfactory-based social interactions ( p < 0.05) and greater non-olfactory mounting ( p < 0.05). However, there were no changes in anxiogenic behavior using the elevated plus maze ( p > 0.05). Post mortem analyses revealed that DHS animals had a loss of oxytocin (OT)-containing cells in the paraventricular nucleus in the hypothalamus (PVN; p < 0.05) as well as an increase in calcitonin-gene related peptide (CGRP; p < 0.05, one tailed ) processes in the central nucleus of the amygdala (CeA) on PND 198. These results may correspond to hypothalamic and amygdalar changes in the human condition and suggest that the hyperserotonemia model of autism may be a valid model which produces many of the social, behavioral, and peptide changes inherent to autism.
S100B is a calcium-binding protein found within astroglial cells. When released, S100B has extracellular neurotrophic effects involving the neuronal cytoskeleton. The gene for S100B is located on ...chromosome 21 and levels of the protein are elevated in Down Syndrome (DS) and Alzheimer's Disease (AD). Thus, overexpression of S100B may be related to the cytoskeletal abnormalities seen in these disorders. Transgenic mice overexpressing human S100B were examined for cytoskeletal changes as young (70 days) and aged (200 days) adults, using immunochemical staining of the dendritic associated protein, MAP-2, the growth-associated protein-43 (GAP-43) and the dendritic spine marker, drebrin. As young adults, the S100B transgenic mice exhibited significantly greater MAP-2-immunoreactivity in the hippocampus, however as older adults, the animals exhibited less staining. In both the CD1 control animals and the S100B animals, the immunoreactivity of drebrin increased with age, however there were no significant between group differences. Finally, the older S100B animals showed more GAP-43 staining than the control animals, suggesting that synaptic remodeling could take place, possibly in response to the loss of MAP-2-ir dendrites. Overall, the data suggest that S100B overexpression leads to changes in cytoskeletal markers. The longitudinal effects of S100B overexpression are discussed with relevance to aging and pathology.
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