Phelan–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. We 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. We 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. Despite 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. Our 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.

中文翻译：

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PV 神经元中 Shank3 的缺失与异常行为和神经元功能相关，这些异常行为和神经元功能可通过增加 GABA 信号传导来恢复

费兰-麦克德米德综合征 (PMS) 是一种神经发育障碍，以发育迟缓、智力障碍和自闭症样行为为特征，主要由 SHANK3 基因单倍体不足引起。目前，PMS 尚无具体治疗方法，因此需要更好地了解 SHANK3 功能和大脑中潜在的病理生理机制。我们假设 SHANK3 单倍体不足可能导致抑制系统的改变，这可能与自闭症谱系障碍 (ASD) 模型中观察到的兴奋/抑制失衡有关。对这些神经病理学特征的研究可能有助于揭示经前综合症的发病机制和潜在的治疗干预措施。我们记录了 Shank3Δ11−/− 小鼠视觉皮层的局部场电位和视觉诱发反应。然后，为了了解 Shank3 对抑制性神经元的影响，我们生成了 Pv-cre+/- Shank3Fl/Wt 条件小鼠，其中小白蛋白阳性神经元中的 Shank3 被删除。我们表征了该小鼠模型的表型，并比较了加奈索酮给药前后的表型。我们发现，在初级视觉皮层中，与 Wt 小鼠相比，Shank3 KO 的增益控制发生了变化，表明对锥体神经元的抑制存在缺陷。在咪达唑仑增强 GABAA 受体活性后，这种改变被挽救。行为分析显示，与 Pv-cre+/- Shank3Wt/Wt 小鼠相比，Pv-cre+/- Shank3Fl/Wt 小鼠的梳理、记忆和运动协调能力受损。这些缺陷可以通过加奈索酮（GABAA 受体的正调节剂）来缓解。此外，我们证明加奈索酮治疗还可以改善 Shank3 KO 小鼠的唤起记忆缺陷和重复行为。尽管我们的研究取得了重大发现，但仍然存在一些局限性。首先，PV 神经元中 Shank3 缺失与行为改变之间联系的神经生物学机制需要进一步研究。此外，Shank3 对其他类别抑制性神经元的影响需要进一步探索。最后，加奈索酮的药理活性需要进一步表征，以提高我们对其潜在治疗作用的理解。我们的研究提供的证据表明，Shank3 缺失会导致皮质锥体神经元的抑制反馈发生改变，从而导致皮质过度兴奋和类似 ASD 的行为问题。具体来说，PV 神经元中 Shank3 的细胞类型特异性缺失与这些行为缺陷相关。我们的研究结果表明，加奈索酮可能是治疗经前综合症的潜在药理学方法，因为它能够挽救 Shank3 KO 小鼠的行为缺陷。总的来说，我们的研究强调了研究抑制性神经元的作用以及对经前综合症等神经发育障碍的潜在治疗干预的重要性。