A common feature of mouse models of autism spectrum disorders (ASDs) is an imbalance between excitation and inhibition within circuits of the central nervous system. This imbalance is thought to contribute to disrupted neural function in these disorders, but the ultimate cause of this imbalance remains unclear.

Gina Turrigiano and her colleagues at Brandeis University have identified several neural plasticity mechanisms that normally maintain the excitation/inhibition balance within neural circuits, including a form of synaptic plasticity called ‘synaptic scaling,’ which acts like a synaptic thermostat to keep neuronal activity within the correct range in response to perturbations. Intriguingly, the laboratory has found that synaptic scaling is completely absent in two distinct mouse models of ASDs, loss of MeCP2¹ and loss of SHANK3 function.

Turrigiano and her team propose to test the hypothesis that loss of synaptic scaling is a primary and convergent cause of excitation/inhibition imbalance in these mouse models of ASD. The team plans to use a variety of approaches to test these ideas, and to work in both in vitro systems and freely behaving mice. Further, they aim to determine whether rescue of synaptic scaling in intact brain circuits in freely behaving animals can restore circuit stability. Taken together, these experiments will constitute a comprehensive and rigorous test of the synaptic scaling hypothesis in the genesis of excitation/inhibition imbalances in ASD and could lead to novel avenues for developing therapeutic strategies.