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bioRxiv · 10.1101/2024.09.09.612160

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

Devienne, G.·Vantomme, G.·Huguenard, J.
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Abstract

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders with heterogeneous causes, and are characterized by communication deficits, impaired social interactions, and repetitive behaviors. Despite numerous studies in mouse models focused on pathophysiological circuit mechanisms of ASD in mature animals, little is known regarding ASD onset and its evolution through development. The medial prefrontal cortex (mPFC) is crucial for higher-order cognitive functions and social behavior, thus key to understanding ASD pathology. To explore early developmental disruptions in the mPFC, we used the Shank3 knockout (Shank3-/-) mouse model. 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 within the mPFC and in its projections to the mediodorsal thalamus (MD) at two developmental stages, preweaning (P14) and adulthood (>P55). Our findings reveal early synaptic deficits at P14 both within the mPFC and in its projections to the MD accompanied by alterations in mPFC network activity and reduced excitability of excitatory neurons, overall suggesting hypofunction. Interestingly, behavioral deficits were already detectable by P11, preceding the observation of synaptic changes at P14. By adulthood, these early synaptic and cellular alterations progressed to global dysfunction, characterized by mPFC network hyperfunction and layer 5 pyramidal cell hyperexcitability, accompanied by augmented glutamatergic signaling to MD with enhanced action potential production. These results suggest that early synaptic changes may precede and interact with behavioral deficits, potentially leading to compensatory mechanisms that contribute to more pronounced mPFC dysfunction later in development. This study highlights the complex dynamic progression of mPFC deficits in ASD and emphasizes the potential impact of targeting early synaptic alterations to mitigate later behavioral and cognitive deficits.

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Devienne, G., Vantomme, G., Huguenard, J.. 2024-09-10. Developmental progression of prefrontal circuit dysfunction in a Shank3-/- mouse model of autism spectrum disorder. https://doi.org/10.1101/2024.09.09.612160

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