Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling

Molecular Autism

Research

Silvia Landi¹  Gian Michele Ratto²  Chiara Verpelli³  Alessia Stefanoni³  Carlo Sala³  Jessica Pagano³  Michael Schön⁴  Helen F. Bauer⁴  Tobias M. Boeckers⁵  Gabriele Nardi⁶  Marica Albanesi⁶  Enrico Pracucci⁶ 

[1] CNR, Neuroscience Institute, Pisa, Italy;NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Pisa, Italy;CNR, Neuroscience Institute, Pisa, Italy;NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Pisa, Italy;Padova Neuroscience Center, Università degli Studi di Padova, Padua, Italy;CNR, Neuroscience Institute, Via Follereau 3, 20854, Vedano al Lambro, Milan, Italy;Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany;Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany;DZNE, Ulm Site, Ulm, Germany;NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Pisa, Italy;

关键词: Autism;    Hyperexcitability;    Ganaxolone;    GABA receptor;   

DOI  :  10.1186/s13229-023-00557-2

 received in 2022-12-11, accepted in 2023-06-27,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPhelan–McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions.MethodsWe recorded local field potentials and visual evoked responses in the visual cortex of Shank3∆11−/− mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre+/−Shank3Fl/Wt conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration.ResultsWe found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABAA receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre+/−Shank3Fl/Wt compared with Pv-cre+/−Shank3Wt/Wt mice. These deficits were rescued with ganaxolone, a positive modulator of GABAA receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice.LimitationsDespite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects.ConclusionsOur study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral deficits in Shank3 KO mice. Overall, our study highlights the importance of investigating the role of inhibitory neurons and potential therapeutic interventions in neurodevelopmental disorders such as PMS.

【 授权许可】

CC BY   
© The Author(s) 2023

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