In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field’s increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.
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We thank Mackenzie Howard for discussions. VSS is supported by NIMH (R01 MH100292 and R01 MH106507). JLRR is supported by Nina Ireland, the Simons Foundation (SFARI #309279), NINDS R01 NS34661, NIMH R01 MH081880, and NIMH R37 MH049428.
Conflict of interest
JLRR is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation. VSS receives research funding from Neurona.
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Sohal, V.S., Rubenstein, J.L.R. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry 24, 1248–1257 (2019). https://doi.org/10.1038/s41380-019-0426-0
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