d.   Neurons & Neurochemicals
The brains of autistic subjects show disturbances in many neurotransmitters, primarily serotonin, catecholamines, the amino acid neurotransmitters, and acetylcholine.  Mercury poisoning causes disturbances in these same neurotransmitters:  primarily serotonin, the catecholamines, glutamate, and acetlycholine.
Serotonin:  Serotonin synthesis is decreased in the brains of autistic children and increased in autistic adults, relative to age-matched controls (Chugani et al, 1999), while whole blood serotonin in platelets is elevated regardless of age (Leboyer; Cook, 1990).  Autistic patients frequently respond well to SSRIs as well as Risperidone (McDougal; 1997; Zimmerman et al, 1996). 
Likewise, a number of animal studies have found serotonin abnormalities from mercury exposure.  For example, subcutaneous administration of methylmercury to rats during postnatal development increases tissue concentration of 5-HT and HIAA in cerebral cortex (O’Kusky et al, 1988).
Findings about serotonin abnormalities in mercury literature implicate interactions between mercury and intracellular calcium as well as mercury and sulfhydral groups:
Many researchers have documented disruptions of intra- and extra-cellular calcium in neurons from mercury exposure (Atchison & Hare, 1994), including thimerosal (Elferink, 1999), and calcium metabolism abnormalities have been identified in autism (Plioplys, 1989; Coleman, 1989).
Intracellular concentrations of Ca2+ are critical for controlling gene expression in neurons and mediating neurotransmitter release from presynaptic vesicles (Sutton, McRory et al, 1999).  5-HT re-uptake activity and intrasynaptic concentration of 5-HT are regulatedby Ca2+ in nerve terminals.  Methylmercury causes a rapid, irreversible block of synaptic transmission by suppression of calcium entry into nerve terminal channels (Atchison et al, 1986).  Thimerosal inhibits 5-HT transport activity in particular throughinteraction with intracellular sulfhydryl groups associated with Ca2+ pump ATPase (Nishio et al, 1996), for example, by modifying cysteine residues of the Ca(2+)-ATPase (Sayers et al, 1993; Thrower et al, 1996).
Dopamine:  Studies have found indicationsboth of abnormally high and low levels of dopamine in autistic subjects (Gillberg & Coleman, 1992, p288-9).  For example, Ernst et al (1997) reported low prefrontal dopaminergic activity in ASD children, while Gillberg and Svennerholm (1987) reported highconcentrations of homovanillic acid (HVA), a dopamine metabolite, in cerebro-spinal fluid of autistic children, suggesting greater dopamine synthesis.  Pyridoxine (vitamin B6) has been found to improve function in some autistic patients by lowering dopamine levels through enhanced DBH function (Gillberg & Coleman, 1992, p289; Moreno et al, 1992; Rimland & Baker, 1996).  Dopamine antagonists such as haloperidol improve some antipsychotic symptoms in ASD subjects, including motor stereotypies (Lewis, 1996).
Rats exposed to mercury during gestation show major alterations in synaptic dynamics of brain dopamine systems.  The effects were not apparent immediately after birth but showed a delayed onset beginning at the time of weaning (Bartolome et al, 1984).  Avariety of mercuric compounds increase the release of [3H]dopamine, possibly by disrupting calcium homeostasis or calcium-dependent processes (McKay et al, 1986). 
Minnema et al (1989) found that methylmercury increases spontaneous release of [3H]dopaminefrom rat brain striatum mainly due to transmitter leakage caused by Hg-induced synaptosomal membrane permeability.  SH groups may also be involved in the inhibition of dopamine binding in rat striatum (Bonnet et al, 1994). Pyridoxine deficiency in rats causes acrodynia, with features similar to human acrodynia (Gosselin et al, 1984).
Epinephrine and norepinephrine:  Studies on autistic subjects have consistently found elevated norepinephrine and epinephrine in plasma, which suggests elevated levels of these transmitters in brain, as plasma and CSF norepinephrine are closely correlated (Gillberg and Coleman, 1992, p.121-122).  Recently, Hollander et al (2000) have noted improvement in function in about half of their ASD subjects with administration of venlafaxine, a norepinephrine reuptake inhibitor.  Mercury also disrupts norepinephrine levels by inhibiting sulfhydryl groups and thus blocking the function of O-methyltransferase, the enzyme that degrades epinephrine (Rajanna and Hobson, 1985).  In acrodynia,blocking this enzyme resulted in high levels of epinephrine and norepinephrine in plasma (Cheek, Pink Disease Website).  In rats, chronic exposure to low doses of methylmercury increased brain-stem norepinephrine concentration (Hrdina et al, 1976).
Glutamate:  It has been observed that many autistics have irregularities related to glutamate (Carlsson ML, 1998).  In autism, glutamate and aspartate have been found to be significantly elevated relative to controls (Moreno et al, 1992); and in a more recent study of ASD subjects, plasma levels of glutamic acid and aspartic acid were elevated even as levels of glutamine and asparagine were low (Moreno-Fuenmayor et al, 1996).
Mercury inhibits the uptake of glutamate, with consequent elevation of glutamate levels in the extracellular space (O’Carroll et al, 1995).  Prenatal exposure to methylmercury of rats induced permanent disturbances in learning and memory which could be partially related to a reduced functional activity of the glutamatergic system (Cagiano etal, 1990).  Thimerosal enhances extracellular free arachidonate and reduces glutamate uptake (Volterra et al, 1992). Excessive glutamate is implicated in epileptiform activities (Scheyer, 1998; Chapman et al, 1996), frequently present in both ASD and mercurialism (see below).
Acetylcholine:  Abnormalities in the cortical cholinergic neurotransmitter system have recently been reported in a post mortem brain study of adult autistic subjects (Perry et al, 2000).  The problem was one of acetylcholine deficiency and reduced muscarinic receptor binding, which Perry suggests may reflect intrinsic neuronal loss in hippocampus due to temporal lobe epilepsy (see section below for discussions of epilepsy and ASD/Hg).  Mercury alters enzyme activities (Koos and Longo,1976, p.400), including choline acetyltransferase, which may lead to acetylcholine deficiency (Diner and Brenner, 1998), or Hg may inhibit acetylcholine release due to its effects on Ca2 homeostasis and ion channel function (EPA, 1997, p.3-79). 
In rats,chronic exposure to low doses of methylmercury decreased cortical acetylcholine levels (Hrdina et al, 1976).  Methylmercury has also been found to increase spontaneous release of [3H]acetylcholine from rat brain hippocampus (Minnema et al, 1989) and to increase muscarinic cholinergic receptor density in both rat hippocampus and cerebellum, suggesting upregulation of these receptors in these selected brain regions (Coccini, 2000).
Demyelination:  Evidence of demyelination has been observed in the majorityof autistic brains (Singh, 1992).  This is true of mercury poisoning as well.  Mild demyelinating neuropathy was detected in two girls (Florentine and Sanfilippo, 1991), and an adult showed axonal degeneration with Hg-related demyelination (Chu et al, 1998).  Methylmercury can alter the fatty acid composition of myelin cerebrosides in suckling rats (Grundt et al, 1980).
 

e.   EEG Activity/Epilepsy

Abnormal EEGs are common in mercury poisoning as well as autism.  In one study, half the autistic children expressed abnormal EEG activity during sleep (reviewed in LeWine, 1999). Gillberg and Coleman (1992) estimate that 35%-45% of autistics eventually develop epilepsy. A recent study by LeWine and colleagues (1999) using MEG found epileptiform activity in 82% of 50 regressive-autistic children.  EEG abnormalities in autistic populations tend to be non-specific and consist of a variety of epileptiform discharge patterns (Nass, Gross, and Devinsky, 1998).
Unusual epileptiform activity has been found in a variety of mercury poisoning cases (Brenner & Snyder, 1980).  These include (i) the Minamata outbreak - generalized convulsions and abnormal EEGs (Snyder,1972); (ii) methylmercury ingestion through contaminated pork - all four affected children had epileptiform features and disturbances of background rhythms; two had seizures (Brenner & Snyder, 1980); (iii) mercury vapor poisoning - abnormal EEG in a 12 year old girl (Fagala and Wigg, 1992) and slower and attenuated EEGs in chloralkali workers with long term exposure (Piikivi & Tolonen, 1989); and (iv) exposure from thimerosal in ear drops and through IVIG - EEG with generalized slowing in an 18 month old girl with otitis media (Rohyans et al, 1984) and a 44 year old man (Lowell et al, 1996).  More recently, Szasz and colleagues (1999), in a  study of early Hg-exposure, described methylmercury’s ability to enhance tendencies toward epileptiform activity and reported a reduced level of seizure-discharge amplitude, a finding which is at least consistent with the subtlety of seizures in many autism spectrum children (LeWine, 1999; Nass, Gross, and Devinsky, 1998).
Processes whereby neuronal damage is induced by epileptiform discharges are elucidated in a number of studies, many of which focus upon brain regions affected in autism.  Importantly, neuronal damage in the amygdala can be an “ongoing delayed process,” even after the cessation of seizures (Tuunanen et al, 1996, 1997, 1999).  Alterations of cerebral metabolic function last long after seizures have occurred.  In a model of seizure-induced hippocampal sclerosis, Astrid Nehlig’s group describes hypometabolism having its regional boundaries“directly connected” to seizure-damaged locus (Bouilleret et al, 2000). 
That Hg increases extracellular glutamate would also contribute to epileptiform activity (Scheyer, 1998; Chapman et al, 1996).
These findings support a rationale:
In susceptible individuals, mercurycan potentiate or induce Hg-related epileptiform activity, which can have lower amplitude and be harder to identify.  Furthermore, this low-level but persisting epileptiform activity would gradually induce cell death in the seizure foci and in brain nuclei neuroanatomically related to the seizure foci.
These studies have a more direct relevance to the possibility of Hg-induced cases of autism (i) because the amygdala are implicated in regard to core traits in autism, as described above, and (ii) because mercury finds its way into the amygdala (see above).  Furthermore, these theoretical relationships are consistent with SPECT imaging studies by Mena, Goldberg, and Miller, who have demonstrated areas of regional hypoperfusion neuroanatomically associated with trait deficits in autism-spectrum children (Goldberg et al, 1999).

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