Too Much of a Good Thing?

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Science Translational Medicine  27 Nov 2013:
Vol. 5, Issue 213, pp. 213ec198
DOI: 10.1126/scitranslmed.3008071

Mutations and deletions in the SHANK3 gene, which encodes a scaffolding protein that colocalizes with excitatory postsynaptic markers, have been linked to autism and schizophrenia. Now, Han et al. describe an association between SHANK3 overexpression and hyperkinetic behaviors that may explain important aspects of mania and related conditions.

Han et al. studied transgenic mice that carried an extra copy of SHANK3. These mice exhibited several behaviors resembling aspects of mania, such as increased locomotion, exaggerated responses to amphetamines, increased startle responses to acoustic stimuli, and abnormal circadian rhythmicity. Notably, these mice also exhibited phenotypes typically associated with antidepressant treatment and autism: decreased immobility in the tail suspension test and reduced preference for social interactions, respectively. Last, mice overexpressing SHANK3 also had spontaneous seizures. The authors then described mechanisms that could have contributed to these phenotypes, such as an increase in markers for synaptic excitation and a corresponding decrease in those for synaptic inhibition. Additional data suggested that these changes may have been due to recruitment by Shank3 of actin-related proteins toward excitatory synapses and away from inhibitory ones. Two final aspects of this study suggested some clinical implications. First, many abnormal behaviors in SHANK3-overexpressing mice were rescued by the anticonvulsant and mood stabilizer valproic acid, but not by lithium. This is notable because although lithium represents the gold-standard treatment for mania, a subpopulation of patients with bipolar disorder respond to valproic acid but not to lithium. In their study, Han et al. also reported on two individuals with small duplications of the genomic region containing SHANK3: a child with seizures and attention deficit hyperactivity disorder (ADHD) and an adult with bipolar disorder and epilepsy.

Taken together, these findings suggest that overexpression of SHANK3 may be associated with hyperexcitability at the neuronal level and hyperactivity at the behavioral level. Interestingly, these behaviors cut across traditional diagnostic categories, encompassing features of many disorders, including mania, ADHD, epilepsy, and autism. Thus, these findings illustrate how viewing disorders from a genetic standpoint, in addition to traditional diagnostic formulations, may help to identify appropriate treatments. Important questions remain; for example, does SHANK3 overexpression or deletion impair social behavior through similar or distinct mechanisms? Another major challenge will be understanding why hyperkinetic phenotypes are prominent in mice overexpressing SHANK3 but not in other contexts that are also associated with increases in synaptic excitation.

K. Han et al., SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 503, 72–77 (2013). [Pub Med]

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