Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by autism and epilepsy and is caused by mutations in one of the two TSC genes (TSC1 and TSC2). Now, Wyatt B. Potter et al. report that aberrant signaling through the glutamate receptor mGluR5 is responsible for the dysfunction in synaptic plasticity that causes the neurological manifestations of the disease (PLOS Biol. 11, e1001627 ).

Changes in synaptic strength occur during learning and development. But when this synaptic plasticity does not occur normally, it can result in epilepsy or in behavioral inflexibility because of the inability to unlearn a behavior.

Synaptic plasticity has previously been reported to be reduced in juvenile Tsc2-deficient mice. Potter et al. found that it is then restored in adult Tsc2-deficient mice, but that this is as a result of aberrant compensatory upregulation of the expression and activity of mGluR5. This enhanced mGluR5 activity had a role in the epileptic and autistic phenotypes in Tsc2-deficient mice: an mGluR5 antagonist could reduce epileptic activity in the brains of the mice and could prevent their autistic-like perseverative behaviors. These findings suggest that inhibiting mGluR5 could be a potential therapeutic approach to treat TSC in humans.