Many disparate clues have recently come to suggest that abnormal nerve cell calcium signaling may somehow be involved in autism. While calcium signaling is an intensely studied biophysical phenomenon that is well recognized to play a central role in many aspects of cell biology and synaptic physiology, its role in disease processes is only beginning to emerge. In fact, recent developments in this area placed within reach a disease-focused symposium on this problem for the first time, and allowed Autism Speaks to award the organizers of this symposium, Drs. Ilya Bezprozvanny from University of Texas at Dallas and J. Jay Gargus from University of California at Irvine, support for this first U.S. meeting focused exclusively on the pathological aspects of calcium signaling.

The organizers, under the auspices of the Society of General Physiologists, brought some of the established leaders in the calcium signaling field who have made significant contributions to disease-related projects together with a number of "rising stars" from the junior faculty plus a cadre of trainees, with the hope that by promoting an exchange between traditional calcium signaling researchers and disease researchers the meeting would play an important role in accelerating progress in the field and its translation into clinical insights and practice. The meeting represented 37 talks and 87 submitted papers and was held from September 3 to 7 for approximately 130 international researchers at the Marine Biological Laboratory in Woods Hole, MA – a renowned historical center for biological research.

The program was very diverse – building upon known biophysical abnormalities in calcium signaling in cardiac and skeletal muscle diseases (such as those underlying arrhythmia, sudden death syndrome, malignant hyperthermia and muscular dystrophy), as well as those causing neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's. It then extended this groundwork to more recent discoveries in a variety of disorders of the central nervous system including migraine, autism, and other neuropsychiatric diseases.

An enormous amount of new data was presented and vigorous discussions took place during the talks and at the abstract poster presentations of the meeting. The hope is that these interactions will foster a number of productive collaborations between traditional "calcium signaling" researchers and clinical scientists interested in autism.


Listed below are select science highlights from the symposium that provided particularly exciting insights into autism:

Ege Kavalali, Ph.D. (UT Southwestern Medical Center at Dallas) described the syndromic form of autism found in patients with Rett syndrome, and presented findings in neuron function using the Rett model MeCP2 knock-out mouse. He found that excitatory synapses in the model showed less spontaneous activity than control mice. This suggests that a defect may lie in the calcium-dependent processes of excitatory neurosecretion and synaptic vesicle trafficking, a process he further showed to be modified by histone deacetylases. This work complemented an abstract by Thomas Sudhof, Ph.D. (HHMI) that connected autism-associated mutations in neuroligins to molecular alterations in synaptic function.

Richard Tsien, Ph.D. (Stanford University School of Medicine) covered Timothy Syndrome, a dominant genetic disorder of which close to 80% of the individuals show evidence of autism. He described how a specific mutation in one specific calcium channel (CACNA1C) has been found to cause this distinctive constellation of autism and a cardiac disease which was long-established to be caused by abnormal ion channel function (called Long QT arrhythmia). He described how the discovery that these two disorders result from a simple ion channel mutation has helped create a strong footing for now analyzing autism, like Long QT, as a disease in calcium channel function. Pamela Sklar, M.D., Ph.D. (Harvard) presented findings from large genome-wide association tests that showed this same CACNA1C calcium channel gene to be strongly associated with Bipolar disease and that more detailed analysis provided further support for the involvement of related genes in this pathway in that disease. Jing Du, Ph.D. (NIMH) provided further support for the role of functional defects in a calcium signaling pathway in Bipolar disease. The particular signaling pathway extends from the plasma membrane to the intracellular calcium stores of the endoplasmic reticulum (ER) and the mitochondria. Interestingly, the process appears to be influenced by a variant of the Bcl-2 gene that had previously been associated with the disease.

Yu-Qing Cao, Ph.D. (Washington University School of Medicine) presented studies on neurological disease caused by mutations in a close-relative of the Timothy Syndrome channel, CACNA1A. She demonstrated functional defects caused by the dominant mutations that underlie Familial Hemiplegic Migraine (FHM) type 1, and extended that work into mouse mutant models, where she showed that disease-causing mutations produce a loss of the channel function in pain nerve fibers. Moreover, this also resulted in other calcium channel types coming to be over-expressed in their place, further perturbing nerve function. J. Jay Gargus, M.D., Ph.D. (University of California, Irvine, School of Medicine) presented studies on FHM type 2 and showed how dominant mutations in the gene for the ATP1A2 ion pump also produce alterations in neuronal calcium signaling by suppressing internal calcium release from ER stores. Most importantly for autism, he further discussed the similarity of newly discovered SCN1A sodium channel mutants causing FHM type 3 with mutations in that same gene that had previously been found in familial autism. Intriguingly, both the FHM3 and autism mutations alter the same domains of the ion channel protein and may have relatively minor impact on its function, whereas other mutations of the gene that produce much more profound structural alterations of the protein have been associated with familial epilepsy.

A broader analysis of calcium signaling defects in common neurodegenerative diseases helped establish the context for extending this work to potential autism-related calcium signaling. Grace Stutzmann, Ph.D. (Rosalind Franklin University of Medicine and Science) focused on comparing calcium signaling abnormalities in brain slices of three separate Alzheimer's disease transgenic mouse models, and Ilya Bezprozvanny, Ph.D. (UT Southwestern Medical Center at Dallas) and Kevin Foskett, Ph.D. (University of Pennsylvania) discussed mechanisms by which the Presenilin proteins (mutated in Alzheimer's) function to alter ER calcium leak.

Another common theme during the presentations on the role of calcium-signaling in neurodegenerative diseases was the impact upon mitochondrial functioning. Lynn Raymond, Ph.D. (University of British Columbia, Canada) performed a systematic evaluation of striatal GABAergic neurons from mouse models of Huntington's disease. She found that the toxic form of the huntingtin protein increased mitochondrial depolarization in response to NMDA receptor calcium signals, leading to apoptosis. James Surmeier, Ph.D. (Feinberg School of Medicine, Northwestern University) discussed his recent findings on the importance of the Timothy Syndrome-related calcium channel CACNA1D in pacemaker activity of the substantia nigra dopaminergic neurons that are vulnerable in Parkinson's disease. He described the demands the calcium signals driven by this pacemaker channel place on mitochondria, and further showed in a mouse toxin model of Parkinson's that clinically approved blockers of this channel spare the mitochondria and are neuroprotective. The role of the mitochondria in calcium signaling disease was extended by a talk of Gyorgy Hajnoczky, Ph.D. (Thomas Jefferson University) who presented his work focused on the role of mitochondria in the calcium signaling abnormality involved in malignant hyperthermia, and by a submitted paper from Mark Mattson, Ph.D. (National Institute on Aging, NIH) that developed a connection between oxidative stress and perturbed calcium homeostasis in Alzheimer's disease. He showed that neurons under oxidative and metabolic stress initially respond by stabilizing cellular calcium homeostasis, but that continued stress causes signaling mechanisms to fail resulting in synaptic dysfunction and cell death.