Zhang Lingzhi, Geng Chi, Li Shan, Tang Qingnan, Liu Penglai, Liu Wei, Qiu Gaoxue, Li Anan, Hu Ankang, Chen Fengjiao
Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, China.
The Animal Facility of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
Neuropsychopharmacology. 2025 Apr;50(5):798-807. doi: 10.1038/s41386-024-02027-6. Epub 2024 Nov 16.
Previous studies indicated that ASD-related olfactory dysfunctions are rooted in the piriform cortex. However, the direct evidence supporting a causal link between the dysfunction of the piriform cortex and olfactory disorders in ASD is limited. In the present study, we explored the role of anterior piriform cortex (aPC) in ASD-related olfactory disorders by specifically ablating Fmr1, a leading known monogenic cause for ASD, in the pyramidal neurons. Our data demonstrated that the targeted deletion of Fmr1 in aPC pyramidal neurons was sufficient to induce deficits in olfactory detection. In vivo and in vitro electrophysiological recordings showed that the deletion of Fmr1 increased the activity of pyramidal neurons, exhibiting an enhanced excitatory response and a reduced inhibitory response upon odor stimulation. Furthermore, specific deletion of Fmr1 enhanced the power of beta oscillations during odor stimuli, meanwhile, disturbed excitatory and inhibitory synaptic transmission. The abnormal morphology of pyramidal neurons induced by the deletion of Fmr1 may be responsible for the impaired aPC neuronal function. These findings suggest that dysfunction of the aPC may play a role in olfactory impairments observed in ASD models related to Fmr1 deficiency.
先前的研究表明，与自闭症谱系障碍（ASD）相关的嗅觉功能障碍源于梨状皮层。然而，支持梨状皮层功能障碍与ASD嗅觉障碍之间存在因果关系的直接证据有限。在本研究中，我们通过特异性敲除锥体神经元中导致ASD的主要已知单基因病因Fmr1，探讨了前梨状皮层（aPC）在与ASD相关的嗅觉障碍中的作用。我们的数据表明，aPC锥体神经元中Fmr1的靶向缺失足以诱导嗅觉检测缺陷。体内和体外电生理记录显示，Fmr1的缺失增加了锥体神经元的活性，在气味刺激时表现出增强的兴奋性反应和减弱的抑制性反应。此外，Fmr1的特异性缺失增强了气味刺激期间β振荡的功率，同时扰乱了兴奋性和抑制性突触传递。Fmr1缺失诱导的锥体神经元形态异常可能是aPC神经元功能受损的原因。这些发现表明，aPC功能障碍可能在与Fmr1缺乏相关的ASD模型中观察到的嗅觉损伤中起作用。
