Associate Professor of Medical Genetics, Duke University School of Medicine
The best bet: “The considerable clinical and molecular heterogeneity observed in autism spectrum disorders poses a significant challenge to develop a strategy for treatment. An important question in the field is whether there is a shared common neural mechanism at synaptic or circuit levels among ‘autisms’ caused by different molecular defects.
The case of a SHANK family gene causing autism offers the best opportunity we have now to determine whether there is a shared mechanism among SHANK1, SHANK2 and SHANK3 in causing autism.”
Step one: “Understand the expression pattern of SHANK family genes at a cellular level. SHANK family genes share a similar but also distinct pattern of expression in the brain during development at the macroscopic level. However, the details and specifics of the cellular pattern of expression in the entire brain are not known. The important question to ask is whether there are overlapping expression patterns at the cellular level among SHANK family genes. This information will then guide the selection of targeted synapses in SHANK-deficient mice.”
Step two: “Determine whether the deficiency of SHANK family genes results in a change of a common synaptic protein complex. The identification of a common scaffold disrupted in SHANK1-, SHANK2-, and SHANK3-deficient neurons or synapses will certainly shed light on a shared mechanism.”
Step three: “Using the brain network instead of a synapse-specific approach. Due to the molecular complexity of SHANK family genes as observed in SHANK3, it is almost certain that the function of SHANK3 in different synapses will be different. The analytic paradigm currently used in autism mouse models mostly focuses on a certain type of synapse in a particular region. The finding from studying one type of synapse may not be generalized and used for developing interventions. Alternatively, one could argue that a novel analytic paradigm that could analyze the network activity in many brain regions simultaneously would be an ideal approach.”