Autism Calcium Channelopathy
Abnormalities in neurotransmitter systems have frequently been recorded in autism. Clinical observations include both elevated and lowered levels of various neurotransmitters compared to controls, including alterations in monoamine metabolism [3654486, 2653386, 3215884], neurotransmitter peptides [9018016, 9315980], with considerably raised levels of beta-endorphin (for vasopressin/oxytocin see Hormones) and altered activities of cholinergic receptors, with binding of muscarinic M(1) receptor being up to 30% and that of nicotinic receptors being 65%-73% lower in the autistic group compared to controls . Postmortem brain examination noted abnormalities of the glutamate neurotransmitter system in autism, with specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum . Expression of several types of GABA receptors is altered in brains of subjects with autism, with levels being significantly reduced in autism compared to controls [18821008, 19002745].
Dysregulations of serotonergic systems in particular have been documented, such as abnormalities in brain serotonin sythesis, with significant reductions in synthesis capacity compared to controls [10072042, 9382481], while at the same time plasma levels of serotonin and free thryptophan appear to be on average 30-50% percent higher in individuals with autism . Autoantibodies to serotonin receptors  and reduced receptor binding have also been recorded . Of note is that one study found correlation of elevated plasma serotonin levels and the the major histocompatibility complex (MHC) types associated with autism .
Calcium influx through VGCCs is a key step in secretion of neurotransmitters, for example serotonin . Due to vesicle priming in neuronal excytosis, the influx of calcium ions is all that is needed to trigger nearly instantaneous neurotransmitter release in neurons . Moreover, some findings indicate that its excessive entry through LTCC during early development may to alter neuronal response properties at later ages . Especially in developing brain modulation of neurotransmitter release by dihydropyridine-sensitive calcium channels involves tyrosine phosphorylation. As the neurons develop a network of neurites, both tyrosine phosphorylation and LTCC activity seem to decrease [9987031, 11226706] (see Brain). This transmitter-secretion effect of LTCC is G-protein-linked and sensitive to pertussis toxin treatment . Influx of calcium through N-type VGCC directly stimulates dopamine release and this effect can be attenuated by chalcium channels blockers [11769325, 15272204]. The involvement of LTCC-linked IP3-sensitive intercellular stores in the calcium-triggered release of dopamine and acetylcholine has also been observed . Secretion of beta-endorphin, whose levels are significantly elevated in autism, is also triggered by calcium influx into the cell and can be lowered in vitro by applying calcium channel blockers [2428932, 10371405].
Following the findings of significant modifications of catecholamine metabolites in autism it may be worth mentioning that the activities of Catechol-O-methyl transferase (COMT), an enzyme involved in the breakdown of the catecholamine neurotransmitters, are inhibited by raised calcium levels in tissue . Additionally, a small pilot study examining administration of tetrahydrobiopterin (R-BH4), a cofactor for tyrosine hydroxylases in the pathway of catecholamines and serotonin, reported amelioration of several autistic traits in study subjects. Decreased dopamine D2 receptor binding was also reported (see below) . Tyrosine hydroxylase (TH) is an enzyme of central importance in catecholamine biosynthesis and the expression level of its gene is controlled by several calcium signalling pathways, most importantly LTCC-regulated CREB (see Brain) [15001085, 9645965]. In so called Tottering mice, an animal model with inherited mutation in calcium channels, the increased density of LTCC in the brain is followed by abnormal regulation of tyrosine hydroxylase. In vivo chronic nimodipine treatment was shown to significantly reduce the expression of TH mRNA in these mice .
In vivo application of calcium channel agonist and antagonists points to a possible role played by calcium inward currents in synthesis and metabolism of dopamine and serotonin in brain, with different effect observed in specific areas of rodent brain [7683338, 2431107, 7545305]