It is proposed that dysregulated calcium signalling, mainly through
disturbances in VGCC function and downstream signalling pathways,
is the central molecular event that leads to pathologies of autism.
Various genetic and external factors are capable of perturbing
calcium homeostasis during critical stages of development. As
concordance of autism in monozygotic twins is less than 100% and
the phenotypic expression of the disorder varies widely, it is
concluded that non-genetic mechanisms could greatly contribute
to the onset of autism.
Environmental influences and risk factors mentioned in this paper,
such as perinatal hypoxia and exposure to infectious agents and
various environmental toxins, are proposed as possible etiological
agents. Furthermore, genetic polymorphism related to immune function
and inflammatory reactions, such as MIF, and expression of chemokine
receptors, such as CCR2 and others, would make for additional
risk factors, raising vulnerability following exposure in critical
stages of development. A combination of such influences, or combinations
with inherited mutations in calcium signalling pathways or closely
linked proteins, would account for the complexity of autistic
phenotype and severity of symptoms.
Involvement of chemokines, chemokine receptors and their signalling
in inflammatory and neurological disease has become more evident
in recent years. It is becoming increasingly clear that, beyond
their involvement in neuroinflammation, these proteins play an
important role in brain development and function, due in great
part to their ability to modulate functioning of ion channels.
In addition to neurons and brain glia, chemokine receptors are
widely expressed on immune and endothelial cells, and have been
proposed to serve as a bridge linking the immune and nervous systems.
Targeting specific chemokines and chemokine receptors, either
directly or indirectly through activation of related opioid, adenosine,
and vasointestinal peptide receptors, is a novel therapeutic strategy
in both inflammatory and infectious disease. Apart from AIDS-dementia,
Alzheimer's disease and the neuroinflammation associated with
multiple sclerosis, desensitation and/or antagonism of specific
chemokine receptors have been proposed as treatment targets in
inflammatory disorders of gastrointestinal tract. Polymorphisms
in genes that encode these receptors are now known to determine
susceptibility to neurological dysfunction in HIV-infected individuals,
and special attention should be paid to these factors considering
that the symptoms and onset of AIDS-dementia in children are often
identical to more common forms of autism [16101548,
Lastly, antibodies to voltage-gated calcium channels, as well
as to proteins that are able to modulate their function, such
as for example maternal antibodies directed against angiotensin
II type I receptors, could also play an etiological role in autism.
Possiblity of perinatal infection that develops into latent, subclinical
infection, and potential reactivation following an external stressor,
such as vaccination, should not be discounted. Apart from the
risk of reactivation, persistent low-level infection could have
major implications during development due to possible modulation
of calcium signalling pathways in host cell.