Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2 -deficient mice

Abstract

Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity–based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2. Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex

“…Previous work has also linked mPFC E/I balance disruption to impairments in sociability (52, 55), and consistent with this, we found that social preference, which was disrupted by MD inhibition, was also ameliorated by increasing PVI activity. We determined that these disruptions in sociability were not due to increased anxiety in the affected groups, given that both groups with social interaction deficits exhibited an anxiolytic phenotype on the EPM.…”

A multiscale analysis in CD38 −/− mice unveils major prefrontal cortex dysfunctions

“…Social interactions involve a circuit of brain structures that includes PFC, hippocampus, amygdala, or other cortical areas susceptible to be altered in ASD. The E-I balance of the PFC is important for both normal and pathologic social interactions (75,76), and we demonstrate here that both social interactions and the E-I balance of the PFC are dysfunctional in the absence of CD38. Our results in juvenile male mice indicate that a decrease in USV emission rate (77) preceded the social alterations seen in adults.…”

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

“…Of note, alterations in inhibitory network activity can lead to an imbalance between excitatory and inhibitory currents (E/I balance), a mechanism that likely underlies ASD (Nelson & Valakh, 2015). In this regard, the reduction of the E/I balance in Cntnap2 KO mice was able to acutely rescue their hyperactivity and deficits in social behavior (Selimbeyoglu et al, 2017).…”