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Clinical findings in autism and relevance of dysfunctional calcium signalling in

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

Dysregulating Factors:
     Genetic Factors
     Infectious Agents





Summary of abnormal biomedical findings in autism

Disturbances in calcium signalling and implications for cerebral blood flow, edema and Blood Brain Barrier in autism

Results of several studies have shown abnormal platelet reactivity and altered blood flow in children with autism. Following these findings it has been suggested that platelet and vascular endothelium activation could be one of the contributing factors to the development and clinical manifestations of the disorder [16908745]. Relative to this the following case reports are of particular interest, both describing cases of inflammation of brain blood vessels resulting in loss of language and emergence of symptoms of autism. In both cases administration of nicardipine lead to recovery of language and behaviour [1373338, 11008286].

PET and SPECT scans in autistic children show a decreased cerebral blood floow in some regions of the brain [12077922, 10960047] and cerebral water content was found to be raised in brain grey matter in children with autism [16924017]. A model has been suggested in which the observed gray matter abnormality could be inflammatory (see Immunity-Inflammation). This finding of celebral edema at the same time offered an alternative explanation for enlarged brain size in autism, which up to then had been hypothesised to be due to lack ‘pruning’ of neurons during development.

For many vessels, including cerebral arteries, calcium entry through LTCC constitutes the main fraction of contractile calcium. This is particularly true for immature cerebral arteries, which are totally dependent on calcium influx through LTCC channels for contraction, due to relative lack of intercellular calcium stores, and in which the expression of these channels is twice as high as in the adult arteries [11742831]. One of possible mechanisms through which excessive calcium influx via LTCC could be causing restricted blood flow is through its effect on synthesis rate of endothelin-1, a potent vasoconstrictor in microvascular endothelial cells [12388093]. Abnormal regulation of L-type calcium channels is directly responsible for abnormal proliferative responses in vascular smooth muscle in various forms of cerebral arteriolar injury associated with endothelial dysfunction [14724353].

Following these findings, a scenario can be suggested in which disturbances in the functioning of LTCC can easily lead to vasoconstriction and decreased cerebral blood flow, as observed in autism.

In an experimental animal model of hydrocephalus and chronic cerebral ischemia, protective effect against declines in motor and cognitive behavior exerted by nimodipine, a LTCC blocker, was thought to be most likely based on improved blood flow [11354411]. Several other calcium channel antagonists have shown various degrees of neuroprotection through improvement of cerebral blood circulation [9877076].

In relation to increased water content in the brain (brain edema), one critical event in its development is breakdown of tight endothelial junctions which make up the blood-brain barrier (BBB), which allows fluid to penetrate into brain. Calcium plays a major role in endothelial junctions, whose function is necessary for the barrier characteristics of cerebral microvessels. G-proteins and several calcium linked proteins and enzymes also seem to be closely involved in junction formation and maintenance [12053015, 1920385]. Calcium ions could therefore alter BBB junction integrity through various signalling cascades, as well as through direct interaction with junction proteins. Regulation of extracellular and intracellular calcium levels seems to be critical in the normal functioning of the BBB.

Several proinflammatory mediators, including various cytokines and chemokines, have direct and indirect effects on the BBB leading to BBB disruption [16671502]. Humal endothelial cells express functional chemokine receptors [9461627, 10479649] that can influence calcium homeostasis via LTCC, leading to disruption of endothelial cellular function. In particular the expression of chemokine receptor CCR2 in human celebral endothelial cells, with its important role in regulating brain endothelial permeability, has been uncovered recently [16192992]. Its ligand, monocyte chemoattractant protein-1 (MCP-1) may cause permeability changes human vascular endothelium cells, possibly through reduced tight junctions of vascular endothelium cells [17098977]. Of particular interest should be also the expression of CCR2 receptors in fetal astrocytes, which together with endothelial cells form BBB, and the interactions of these receptors with MCP-1 and calcium signalling [12271471, 15689955]. Disruption of chemokine receptor CCR2 abolished both CNS inflammation and encephalopathy in a murine study [12486156] (also see Immunity-Inflammation and Viruses for more details on chemokine receptors and calcium signalling and findings of excessive levels of MCP-1 in brain and CSF in autism).

These chemokine receptors can be activated by viral proteins, for example the chemokine-like protein from human herpesvirus 6 was found to cause calcium mobilization through the CCR2 receptor. It has been suggested that this protein during reactivation of the virus could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis [12554737]. Infection of mouse epithelial cells with the influenza A-type virus strain strongly induced the expression of CCR2 and CCR5 receptors, followed by a strong monocyte migration [16849492]. In this context it should be mentioned that prenatal influenza infection has been implicated in the etiology of autism (see Viruses).

In the case of the widely studied HIV-1 virus, while its Tat protein is thought to induce polarization of CCR2 receptors in astrocytes [15578658], its protein gp120 has been found to compromises blood-brain barrier integrity by directly altering expression of tight junction proteins in brain microvascular endothelial cells. The mechanism of action behind this effect seems to be linked to its activation of chemokine receptors CCR5, protein kinase C (PKC) pathways and subsequent release of calcium from intercellular stores [16685256].

While for both HIV and HCMV, binding of viral glycoproteins to the cell surface is sufficient to induce a calcium response, herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) affect calcium signalling pathways in endothelial cells by triggering release of calcium from endoplasmic stores via IP3 receptor activation, with subsequent additional rises in calcium levels due to activation of IP3-linked voltage gated membrane channels [14568989].

It may be of interest in this context to note the observation concerning infection level of endothelial cells by human cytomegalovirus (HCMV) being influenced by level of PKC. In other words stimulation of this signalling pathway prior to infection results in an increase of infection by HCMV while its inhibition prevented virus replication in murine studies [9175259, 16033962]. Similar effects have been observed in respect to Epstein-Barr Virus (EBV) replication [2155183] . It should be noted that calcium is one of the activators of PKC.

In addition to the implications of chemokine-calcium signalling interactions in the endothelial and immune cells, similar events have been suggested to take place in neurons as well, whereas viral protein interference with chemokine receptors is able to influence downstream calcium-linked events, including activation of CREB and interference with cell-cycle proteins in neurons [11880151, 9826729, 12775414]. (see Brain and Viruses).

Apart from viruses and bacteria, several toxic agents have been shown to directly interfere with calcium homeostasis in endothelium, thus contributing to their neurotoxic effects. For example exposure of cerebral vascular smooth muscle to methanol results in significant elevation in intercellular calcium. This methanol-induced cerebral vasospasm as a consequence of large rises in calcium levles is thought to play a central role in methanol-induced cerebral edema, brain hemorrhage, and cerebral and retinal infarcts, resulting in severe deficits in brain blood flow and disturbances of the CNS [10456574]. Similarly, many of the neurotoxic effects of lead are supposed to be related to its ability to dysregulate calcium signalling in cerebral arteries, leading to breakdown of BBB. Apart from its effects on the endothelial cells, another mechanism by which lead disrupts BBB is by damaging the astrocytes, which together with endothelium form a functional BBB. This damaging effect on astrocytes is also at least partly due to dysregulation of LTCC function by this heavy metal [1671748] (see Toxins). A similar mechanism has been hypothesised to be behind the neurotoxic effect of methylmercury, suggested to be secondary to astrocytic damage and disruption BBB brought about by the compound [15288515].

Relative to the function of astrocytes in maintenance of BBB, cerebral blood flow and cerebral edema, the role of brain aquaporins in regulation of water homeostasis and the cerebro spinal fluid formation should be mentioned. Perturbed water flow via brain aquaporins has been implicated in many neurological diseases [15561405, 15561410] and the involvement in the brain edema formation of several aquaporins that are abundantly expressed in astrocytes, at the blood brain barrier, has been reported recently. Calcium is known to play a role in expression of aquaporins and the involvement of LTCC in aquaporin functioning has been implicated in several studies [11353665] and calcium signalling and its effects on vasoconstriction by astrocytes is one of the mechanism for the regulation of cerebral blood flow [15356633]. Of interest are the increased levels of brain aquaporin 4 in autism [18435417].

Calcium overload therefore plays an important role in the occurrence and development of brain water edema. Treatment with nimodipine can dramatically reduce the damage of acute infectious brain edema induced by administration of pertussis toxin and thought to involve the opening of calcium channels in endothelial and neuronal cells. This effect is thought to be partially due to the reduction of the disruption of BBB by this calcium antagonist, although the opposite effect has been observed in acute brain damage, in which nimodipine treatment intensified edema formation [12659709, 9868080, 2118717, 3312189]. Benidipine, another calcium channel blocker, is also shown to restore endothelial function under particular circumstances [16172001].

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HIV and Autism