Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABA_A signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.

SIGNIFICANCE STATEMENT Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder (ASD), manifests severe neurodevelopmental delays. Likewise, FXS disease models display disrupted neurodevelopmental critical periods. In the well-mapped Drosophila olfactory circuit model, perturbing the causative fragile X mental retardation protein (FMRP) within a single olfactory sensory neuron (OSN) class impairs odorant-dependent remodeling during an early-life critical period. Importantly, this impairment requires activation of other OSNs, and the olfactory circuit can compensate when FMRP is removed from all OSNs. Understanding the neuron-specific FMRP requirements within a developing neural circuit, as well as the FMRP loss compensation mechanisms, should help us engineer FXS treatments. This work suggests FXS treatments could use homeostatic mechanisms to alleviate circuit-level deficits.

关键时期是神经回路有效适应新感觉环境的发育窗口。脆性 X 综合征 (FXS) 的动物模型是一种常见的单基因自闭症谱系障碍 (ASD)，表现出感官体验驱动的关键时期的严重损伤。然而，目前尚不清楚致病性脆性 X 智力迟钝蛋白 (FMRP) 是否在神经元中均匀起作用，或者表现出神经元特异性功能。在这里，我们使用遗传易处理的果蝇两性的脑触角叶 (AL) 嗅觉回路研究神经元特异性 FMRP 在生命早期关键时期嗅觉感觉神经元 (OSN) 神经支配的气味体验依赖性重塑中的作用。我们发现有针对性的 OSN 类特异性 FMRP RNAi 会损害 AL 突触肾小球内的神经支配重塑，而全局dfmr1空突变体显示出相对正常的气味驱动细化。我们发现 OSN 细胞自主和细胞非自主 FMRP 功能介导气味体验依赖性重塑，AL 电路 FMRP 失衡导致整体肾小球神经支配细化缺陷。我们发现 OSN 类特异性 FMRP 水平双向调节关键期重塑，气味经验选择性地控制 AL 肾小球中的 OSN 突触末端。我们发现特定于 OSN 类的 FMRP 损失通过破坏其他气味反应性 OSN 对横向调制的反应而损害关键期重塑，从而调节整体 AL 增益控制。我们发现沉默谷氨酸能 AL 中间神经元可减少 OSN 重塑，而相反，干扰 OSN 类特异性 GABA _A信号增强重塑。这些发现揭示了具有神经元特异性电路功能的 FMRP 对 OSN 突触重塑的控制，并表明神经电路如何补偿全局 FMRP 损失以恢复正常的关键期脑电路重塑。

意义声明脆性 X 综合征 (FXS) 是智力残疾和自闭症谱系障碍 (ASD) 的主要单基因原因，表现出严重的神经发育迟缓。同样，FXS 疾病模型显示神经发育关键时期中断。在映射良好的果蝇中嗅觉回路模型，扰乱单个嗅觉感觉神经元 (OSN) 类中的致病性脆性 X 智力迟钝蛋白 (FMRP) 会损害早期生命关键时期的气味依赖性重塑。重要的是，这种损伤需要激活其他 OSN，当 FMRP 从所有 OSN 中移除时，嗅觉电路可以进行补偿。了解发育中的神经回路中特定于神经元的 FMRP 要求，以及 FMRP 损失补偿机制，应该有助于我们设计 FXS 治疗。这项工作表明 FXS 治疗可以使用稳态机制来缓解电路水平的缺陷。