Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Abstract

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.

Fig. 1

Top: in a unidimensional framework, E-I balance refers to the overall level of circuit activity. Dysfunction in inhibition (or excessive excitation) may cause balance to occur at an overall higher level of circuit activity. This may effectively decrease the signal to noise ratio, by increasing deleterious signals, i.e., “noise”, which render circuits less responsive to “signals”, i.e., behaviorally meaningful inputs. In this framework, “noise” might represent input that is not meaningful, or alternatively, an excessively high conductance state that produces low neuronal gain in response to signals. Conversely, excessive inhibitory feedback (or deficient excitation) may cause the circuit to achieve balance at an overall lower level of circuit activity, which may effectively reduce the signal to noise ratio by reducing the strength of signals. Bottom: In a more complex framework, E-I balance can be conceptualized as a multidimensional space. Different mechanisms, e.g., abnormal development due to altered gene expression or protein translation, compensatory or homeostatic processes, etc. perturb circuits along multiple dimensions in this space. In the future, biomarkers may be identified which indicate the state of the circuit along specific dimensions