Common circuit defect of excitatory-inhibitory balance in mouse models of autism

TLDR

ASD may be explained by disruption of excitatory/inhibitory circuit balance during critical developmental periods. The study investigated whether Parvalbumin‑positive inhibitory neurons, which normally drive experience‑dependent circuit refinement, are disrupted across heterogeneous ASD mouse models. Researchers performed a meta‑analysis of PV expression in existing ASD mouse models and added analyses of two additional models—prenatal valproate exposure and the Neuroligin‑3 R451C mutation—to assess PV cell alterations. PV‑positive cells were reduced throughout the neocortex in multiple ASD mouse models, with VPA and NL‑3 R451C showing asymmetric hemispheric reductions in parietal and occipital cortices, indicating a shared PV‑circuit disruption that may guide prevention strategies.

Abstract

Abstract One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877–888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism.