BACKGROUND 22q11.2 deletion syndrome (22qDS) manifests with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency make 22qDS symptoms particularly difficult to manage with traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored whether managing this aberrant activity in adults could be a therapeutically beneficial strategy. METHODS To assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific subcircuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion. RESULTS 22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected memory deficits and did so in a regionally specific manner: ventrally targeted constructs rescued only social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally specific manner. CONCLUSIONS These data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove to be an effective therapeutic for treatment-resistant symptoms of mental illness.

中文翻译：

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模块化、基于电路的干预措施在 22q11.2 缺失综合征小鼠模型中拯救海马依赖的社会和空间记忆。

背景 22q11.2 缺失综合征 (22qDS) 表现为多种症状，包括多种神经精神疾病。与多基因单倍体不足相关的并发症使 22qDS 症状特别难以用传统治疗方法控制。然而，不同的机械后果往往最终导致对神经元回路活动的不当调节。我们探讨了在成人中管理这种异常活动是否可能是一种有益的治疗策略。方法 为了评估和剖析海马回路功能，我们在急性切片中进行了功能成像，并针对雄辩回路（与特定行为任务相关的特定子回路）进行了功能成像，以提供相关的行为输出。例如，腹侧和背侧 CA1 区域严重支持社会和空间歧视，分别。我们通过由兴奋性神经元特异性启动子元件驱动的腺相关病毒载体在 34 只对照和 24 只 22qDS 模型小鼠中重点引入了化学遗传学构建体，以按需方式操纵电路募集。结果 22qDS 模型小鼠在社会和空间记忆中表现出 CA1 兴奋性集合过度兴奋和伴随的行为缺陷。值得注意的是，锥体细胞的急性化学遗传学抑制成功地纠正了记忆缺陷，并以区域特定的方式做到了这一点：腹侧靶向结构只能挽救社会行为，而那些在背侧表达的结构选择性地影响空间记忆。此外，操纵对照小鼠的活动可以以区域特定的方式概括记忆缺陷。结论 这些数据表明，即使面对具有强烈发育成分的多基因单倍体不足，重新调整活动失调可以挽救疾病改变回路中的功能。以局部模块化方式靶向电路兴奋性可能被证明是治疗精神疾病难治性症状的有效疗法。