Efrain Charles Azmitia

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.

Stress and anxiety may worsen atopic dermatitis (AD) through the serotonin system. Serotonergic expression was measured in 28 patients with ...

Serotonin was discovered in 1949 and has been detected in all living aerobic organisms and in every tissue of the human body. In animals, serotonin functions both as a neurotransmitter and a trophic factor. As a neurotransmitter, serotonin can modify a variety of biological and behavioural functions, including sex, aggression, appetite, locomotor activity, learning and memory, sleep and hormonal secretion. As a trophic factor, serotonin is involved in the neuronal neurogenesis and neural maturation and has been implicated in the release of the cytoskeletal stability factor, S100b. The trophic actions of serotonin in human foetus begin soon after conception and are dependent on supplies provided by the mother's synthesis of serotonin in the gut by enterochromaffin cells and subsequent transfer in blood platelets. The baby not only gets most of its serotonin from the mother while in the uterus, but also makes serotonin very early in gestation when serotonin neurons appear in the midbrain, and serotonergic fibres soon spread throughout the brain. Serotonin at these early times is a differentiating factor and enhances cell mitosis, migration and maturation in subcortical, cortical and peripheral tissues. Serotonin neurons are sensitive to a large number of trophic, neurotransmitter, hormonal and sensory inputs and it has been proposed that this single chemical system serves as a brain homoeostatic regulatory. It is not surprising that serotonin is implicated in a variety of human illnesses, such as depression, Alzheimer's disease, attention deficit disorder, anorexia nervosa, bulimia, autism and schizophrenia. Therefore, when discussing the function of serotonin, it should be remembered that this molecule is ancient and predates the formation of the nervous system in both phylogeny and ontogeny.Key Concepts: Serotonin is made from oxygen, tryptophan and reducing cofactors by two enzymes: tryptophan hydroxylase and L‐aromatic amino acid decarboxylase. Tryptophan is able to absorb photons from sunlight (blue wave) and convert to biological energy and is essential for photosynthesis; producing oxygen in aerobic cells. Serotonin made in large quantities in plants, where it appears to serve as regulatory mechanism to prevent excess oxygen from damaging cells. Serotonin neurons in the human brain can activate at least 14 separate receptors and activation of the 5‐HT2A receptor by psilocybin, mescaline and lysergic acid diethylamide produces hallucinations. Serotonin in humans is made in a restricted midline area of brainstem called the raphe nuclei and has axonal connections to nearly every region of the brain. Serotonin neurons are born early in gestation by the action of several genes includingPET‐1, a transcription factor specific for this neuronal system. Serotonin acts as a trophic factor regulating cell proliferation, maturation and apoptosis by direct receptor actions as well as release of the glial protein, S100b. A decrease in serotonin neurons is associated with depression and suicide, and neurons show evidence of neurodegeneration in autism, Alzheimer's disease, Parkinson's disease, frontal lobe dementia and Lewy‐body dementia. Serotonin is made within enterochromaffin cells in the gut and collected in blood platelets for transfer to all cells in the body and serves as a vehicle by which the mother can influence the development of her baby. Melatonin is made from serotonin.

Context: Human mastocytosis is a rare disease, in which the serotonergic system may be involved. Objective: The objective of the present study was to examine the possible presence of serotonin (5-HT) and its 5-HT1A receptor (R) in the skin of patients with mastocytosis. In addition, the effect of the 5-HT1AR was tested on human mastocytosis cells, cultured in vitro. Materials and methods: The expression of 5-HT and 5-HT1AR in patients with urticaria pigmentosa and mastocytoma was studied using immunohistochemistry. The effects of 8-OH-DPAT, an agonist of 5-HT1AR, on the proliferation (cell number), viability, apoptosis, spontaneous release of histamine, as well as a possible 5-HT metabolism, in the human HMC-1 mast cell line, were investigated. Results: Both 5-HT and 5-HT1AR were expressed in the mast cells in biopsies of mastocytoma and urticaria pigmentosa, as well as in HMC-1 cells. However, no metabolism of 5-HT by the cell line could be detected by the methodology used. The 5-HT1AR agonist had no significant effect on the viability and number of HMC-1 cells, and was without effect on the apoptosis. At concentrations of 10⁻⁶ mol/L and 10⁻⁸ –10⁻¹⁰ mol/L (i.e. also at physiological concentrations), the agonist inhibited histamine release by these cells by as much as 30%. Conclusion: These findings indicate that 5-HT and its 5-HT1AR are expressed in human mastocytosis and that an agonist of the 5-HT1AR might be of value in the treatment of these patients.

J. Neurochem.(2012)120, 396–407. Aberrant dopamine release in the prefrontal cortex (PFC) is believed to underlie schizophrenia, but the mechanistic pathway through which a widely used antipsychotic, clozapine (Clz), evokes neurotransmitter‐releasing electrical stimulation is unclear. We analyzed Clz‐evoked regulation of neuronal activity in the PFC by stimulating axons in layers IV and V and recording the electrical effect in the post‐synaptic pyramidal cells of layers II and III. We observed a Clz‐evoked increase in population spike (PS), which was mediated by serotonin 1A receptor (5‐HT_1A‐R), phospholipase Cβ, and Ca²⁺/calmodulin‐dependent protein kinase II (CaMKII). Immunoblotting demonstrated that the Clz‐activation of CaMKII was 5‐HT_1A‐R‐mediated. Intriguingly, the NMDA receptor (NMDA‐R) antagonist (±)2‐amino‐5‐phosphonovaleric acid (APV) eliminated the Clz‐mediated increase in PS, suggesting that the 5‐HT_1A‐R, NMDA‐R and CaMKII form a synergistic triad, which boosts excitatory post‐synaptic potential (EPSP), thereby enhancing PS. In corroboration, Clz as well as NMDA augmented field EPSP (fEPSP), and WAY100635 (a 5‐HT_1A‐R antagonist), APV, and a CaMKII inhibitor eliminated this increase. As previously shown, CaMKII binds to the NMDA‐R 2B (NR2B) subunit to become constitutively active, thereby inducing α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptor recruitment to the post‐synaptic membrane and an increase in fEPSP. Co‐immunoprecipitation demonstrated that Clz potentiates interactions among CaMKII, NR2B, and 5‐HT_1A‐R, possibly in the membrane rafts of the post‐synaptic density (PSD), because pretreatment with methyl‐β‐cyclodextrin (MCD), an agent that disrupts rafts, inhibited both co‐immunoprecipitation as well as fEPSP. In summary, Clz functions in the PFC by orchestrating a synergism among 5‐HT_1A‐R, CaMKII, and NMDA‐R, which augments excitability in the PFC neurons of layers II/III.

Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point‐to‐point functional neural systems (e.g., auditory and social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Disorders Research Program, AS073234, Program Project (JW). Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5‐HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5‐HT axons in postmortem brain tissue from autism donors aged 2.8–29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors 8 years of age and up, several types of dystrophic 5‐HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest new therapies may be effective to blunt serotonin's trophic actions during early brain development in children. Anat Rec, 2011.