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Introduction

Clinical findings in autism and relevance of dysfunctional calcium signalling in
:

     Brain Development
     Neurotransmitters
     Hormones
     Motor/Sensory Disturbances
     Blood Brain Barrier
     Epilepsy/Seizures
     Immunity and Inflammation
     Gastrointestinal Issues
     Membrane Metabolism
     Oxidative Stress
     Mitochondrial Dysfunction
     Gender Differences

Dysregulating Factors:
     Genetic Factors
     Hypoxia/Ischemia
     Toxins
     Infectious Agents
     Other

Conclusion

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Summary of abnormal biomedical findings in autism






Autism, hormonal metabolism and calcium signalling


Abnormalities in hormonal metabolism are frequently observed in individuals with autism, with several studies observing abnormal levels of many hormons and their receptors compared to healthy controls, as well as abnormal hormonal secretion rhythms [2713159, 1904373, 12959423, 10808042].

For example the analysis of the Hypothalamic-Pituitary-Adrenocortical (HPA) system responses observed more variable circadian rhythm as well as significant elevations in cortisol following exposure to a novel stimulus in children with autism compared to controls. This exaggerated cortisol response is indicative of dysfunction of the HPA system in autism [16005570]. Over-reaction of the endocrine system to insulin stress in autism has been recorded in another study, whereas the experimental stress of insulin-induced hypoglycemia showed slower recovery of blood glucose, much faster cortisol response and elevation of growth hormone levels compared to controls [1176974, 2870051]. Low levels of insulin-like growth factor-I (IGF-I) in cerebrospinal fluid have also been observed [16904022].

Metabolic disorders of serotonin and dopamine systems have been suggested in autism, with aproximately thirty percent of individuals with autism exibiting high levels of serotonin, simultanous with lowered levels of melatonin (see Neurotransmitters). Melatonin is converted from serotonin by several enzymes of the pinealocytes in the pineal gland, including 5-HT N-acetyl transferase and 5-hydroxyindole-O-methyltransferase. Results of the studies looking at sleep disturbances in autism suggest that both dyssomnias and parasomnias are very prevalent in the disorders - people with autism frequently experience sleep disorders and exhibit atypical sleep architecture [10722958, 15705609, 17001527]. Further evidence of dysfunction of pineal endocrine system in autism was obtained by looking at alterations of the light and dark circadian rhythm of melatonin, where none of autistic patient showed a normal melatonin circadian rhythm, together with once again significantly lower levels of this hormone [11455326].

Leptin is a hormone linked to melatonin that plays an important role in amongst other things regulation of appetite and metabolism. Results from a recent study have demonstrated significant differences in leptin concentrations between children with autism and controls [17347881].

Calcium influx through voltage gated calcium channels is directly involved in both neurotransmitter and hormone secretion. In newborn mice the relative dominance of LTCC over other types of calcium channels has been observed [14724188]. LTCC are present on different pituitary cells and their activity is in part modulated by sex steroids [2461851] (see also Gender Differences). Hormonal secretion evoked by various agents is mediated via calcium influx through LTCC [9514161, 15500542, 8677013, 1649931].

Calcium signalling plays a central role in regulation of melatonin biosynthesis, mostly through activities related to phosphorylation of the transcription factor CREB [9618900] (see Brain for details on LTCC-CREB). Changes in conductance of LTCC and intracellular calcium oscillations have dramatic effects on melatonin levels [10820209] (see also Neurotransmitters– serotonin).

Calcium signalling though LTCC plays an important role in the release of insulin and regulation of the expression of its gene (via CREB mediated transcription). Significantly increased amounts of calcium in the cells cause release of previously synthesised insulin, stored in secretory vesicles (see Gastrointestinal). Of possible relevance is the observation that both low and elevated or sustained levels of intracellular calcium impair insulin-stimulated glucose uptake [2551647, 3312189].

Thus calcium appears to required for glucose utilization and plays an essential role in the stimulatory effect of insulin on leptin secretion. Hoever, excess calcium disrupts leptin secretion by interfering with metabolic events that are independent from glucose uptake [15331383].

Oxytocin is a neuropeptide hormone that also acts as a neurotransmitter in the brain and together with vasopressin, another posterior pituitary hormone, has a role in regulation of social bonding and behaviors in mammals such as mating, pair-bond formation, maternal and parenting behavior, and attachment [16884725]. Rodents lacking the oxytocin or vasopressin gene or those lacking the vasopressin V1a receptor show significant deficits in social behaviour and social recognition [15749248]. It has therefore been suggested that deficiencies in oxytocin pathways in the brain might be a feature of autism. Parallel to the animal model studies actual alterations in endocrine oxytocin system have been observed in children with autism [11690596].

It may be of relevance in this context tha V1a vasopressin receptor is a G-protein coupled receptor functionally tighly linked to LTCC. This coupling is sensitive to pertussis toxin treatment [8913359]. When stimulated by an agonist (vasopressin) this receptor is able to induce a complex intracellular calcium signalling cascade for gene expression in astrocytes, eventually influencing CREB-mediated events and decreasing expression levels of several cytokines, notably interleukin-1beta and tumor necrosis factor-alpha. This V1 agonist-induced decrease of cytokine release from cortical astrocytes was also shown to be neuroprotective in cortical neurons [14999073]. In cultured cortical neurons, V1aR activation again influences the influx of extracellular calcium via regulation of activities of LTCC [11726244]. Oxytocin also seems to be able to regulate calcium currents via LTCC [7530160, 11757073]. On the other hand the opposite mechanism has been observed, whereas entry of calcium through LTCC influences relase rate of vasopressin and oxytocin hormones [7957609]. Even more interesting and of possible relevance to autism is the observation that although the secretion of these two hormones seems to be induced by calcium influx at initial stages, the prolonged activation of LTCC results in decline in their secretion [2072100].







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