Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice

Guo, Baolin; Liu, Tiaotiao; Choi, Soonwook; Mao, Honghui; Wang, Wenting; Xi, Kaiwen; Jones, Carter; Hartley, Nolan D.; Feng, Dayun; Chen, Qian; Liu, Yingying; Wimmer, Ralf D.; Xie, Yuqiao; Zhao, Ningxia; Ou, Jianjun; Arias-Garcia, Mario A.; Malhotra, Diya; Liu, Yang; Lee, Sihak; Pasqualoni, Samuel; Kast, Ryan J.; Fleishman, Morgan; Halassa, Michael M.; Wu, Shengxi; Fu, Zhanyan

doi:10.1016/j.xcrm.2024.101534

Cited by 3 publications

References 76 publications

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

Devienne,

Vantomme,

Huguenard

2024

Preprint

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Autism 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.

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

Devienne,

Vantomme,

Huguenard

2024

Preprint

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Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B^−/−Mice

Shih,

Nelson,

Janeček

et al. 2024

Preprint

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Medial prefrontal cortex (mPFC) dysfunction is associated with cognitive and sensory abnormalities in individuals with autism spectrum disorder (ASD), yet the trajectory of mPFC circuit development in these conditions remains poorly understood. In this study, we investigated the postnatal maturation of glutamatergic connectivity and neuronal excitability in pyramidal neurons (PYR) and parvalbumin-positive interneurons (PVIN) in the mPFC of mice harboring deletions in SHANK3, a well-established genetic cause of autism associated with severe cognitive impairments and seizures. Our findings reveal early deficits in PVIN excitability that precede changes in the synaptic and intrinsic properties of PYR, resulting in impaired feedforward inhibition. In vivo calcium imaging demonstrated hypoactivity of PVIN in dorsal mPFC circuits during early postnatal development, characterized by reduced calcium transients in PVIN. By adulthood, these excitability phenotypes were reversed, with PVIN becoming hyperexcitable and PYR hypoexcitable. These results suggest that early PVIN dysfunction in Shank3B-/- mice emerges during postnatal development and may represent a key pathogenic mechanism and potential therapeutic target in SHANK3-related disorders.

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X chromosome inactivation; motor difficulties in 16p11.2 duplication and deletion; oligodendroglia

Adams

2024

The Transmitter

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Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice

Cited by 3 publications

References 76 publications

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

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

Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B^−/−Mice

X chromosome inactivation; motor difficulties in 16p11.2 duplication and deletion; oligodendroglia

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Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice

Cited by 3 publications

References 76 publications

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

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

Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B−/−Mice

X chromosome inactivation; motor difficulties in 16p11.2 duplication and deletion; oligodendroglia

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

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

Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B^−/−Mice