Developmental progression of prefrontal circuit dysfunction in a Shank3–/–mouse model of autism spectrum disorder

Author:

Devienne GabrielleORCID,Vantomme GilORCID,Huguenard John RORCID

Abstract

AbstractAutism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders with heterogeneous causes, characterized by communication deficits, impaired social interactions, and repetitive behaviors. Despite numerous studies focused on pathophysiological circuit mechanisms of ASD in mature mice, little is known regarding ASD onset and its evolution through development in these models. To explore early disruptions in mPFC development, we utilized the Shank3 knockout (Shank3–/–) mouse model, a well-established genetic model of ASD. The medial prefrontal cortex (mPFC) is crucial for higher-order cognitive functions and social behavior, making it a key brain area of interest for understanding ASD pathology. SHANK3 is crucial for glutamatergic synapse maturation, and the Shank3–/–mouse has been well-characterized for displaying ASD-related behavioral phenotypes. We investigated network, cellular, and synaptic changes in the mPFC at two developmental stages, P14 and adulthood (>P55). Our findings revealed that while differences in neuronal excitability including hypofunction are detectable at P14, global mPFC dysfunction, including network hyperfunction and layer 5 pyramidal cell hyperexcitability, only becomes evident in adulthood. This suggests that early cellular changes that precede the development of behavioral deficits may lead to compensatory mechanisms that contribute to more pronounced mPFC deficits later in development. These results highlight the complex and evolving nature of mPFC dysfunction in ASD and suggest that early synaptic changes may set the stage for later behavioral and cognitive deficits.

Publisher

Cold Spring Harbor Laboratory

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