Excessive levels of calcium mark brains of individuals with Autism

Writing in Molecular Psychiatry, L. Palmieri of the Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari (Bari, IT) and colleagues reported the results of a small-n study of levels of metabolic transporters in the brain tissue of individuals with and without Autism. They compared the contents of samples from the brains of individuals with Autism and individual without Autism (matched on the bases of sex, age, and time after death that the samples were obtained). They found aspartate-glutamate carrier activity was increased by excessive calcium levels in brains of the Autistic individuals.

Note bene: Although the authors speculate about the potential for this finding to lead to therapies, they expressly warn against certain possible applications: “In particular, our findings in no way support the use of [calcium] chelation as a therapeutic approach in autism. [Calcium] chelation has not only been purported of benefit in few anecdotal reports and small-sized open trials, but also carries a substantial risk to produce hypocalcemia, resulting in recent deaths of autistic children.”

Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient–control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca2+). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca2+ chelator ethylene glycol tetraacetic acid; neocortical Ca2+ levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca2+-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca2+ levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca2+ homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

This study originally appeared online in 2008, but even before then, some researchers had speculated that certain forms of Autism may be caused by the chemicals responsible for regulation of neural development. For example, Krey and Dolmetsch (2007) suggested that “mutations of several voltage-gated and ligand-gated ion channels that regulate neuronal excitability and [calcium] signaling have been associated with [Autism Spectrum Disorders; ASDs]. In addition, [calcium]-regulated signaling proteins involved in synapse formation and dendritic growth have been implicated in ASDs.”

Palmieri, L., Papaleo, V., Porcelli, V., Scarcia, P., Gaita, L., Sacco, R.,… & Persico, A. M. (2010). Altered calcium homeostasis in autism-spectrum disorders: Evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Molecular Psychiatry, 15, 38–52; doi:10.1038/mp.2008.63

Krey, J. F., & Dolmetsch, R. E. (2007). Molecular mechanisms of autism: A possible role for Ca2+ signaling. Current Opinions Neurobiology, 17(1), 112-119.