Mancini Andrea, Bellingacci Laura, Canonichesi Jacopo, Sciaccaluga Miriam, Megaro Alfredo, Zianni Elisa, De Carluccio Maria, Pariano Marilena, Emiliano Edoardo, Tozzi Alessandro, Costa Cinzia, Zelante Teresa, Romani Luigina, Viscomi Maria Teresa, Gardoni Fabrizio, Calabresi Paolo, Parnetti Lucilla, Di Filippo Massimiliano
Section of Neurology and Laboratory of Experimental Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Section of Physiology and Biochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Neurobiol Dis. 2025 Sep;213:106994. doi: 10.1016/j.nbd.2025.106994. Epub 2025 Jun 8.
The basal ganglia (BG) network exerts a key role in the integration of cortical inputs and is fundamental to motor learning, behavior, emotional responses, and cognitive functions. Little is known about how immune cells and soluble immune mediators influence BG activity. Interleukin-17A (IL-17A) is in the spotlight for its emerging role as a neuromodulator of cortical synaptic transmission and plasticity in physiological and pathological conditions. However, its role at the level of subcortical structures such as the BG circuit is still unclear. In this study, we demonstrate that striatal medium spiny neurons (MSNs) highly express IL-17RA and that the IL-17 axis contributes to the physiological expression of synaptic plasticity in these cells. Indeed, long-term potentiation (LTP) induction was significantly reduced in mice lacking IL-17A or IL-17RA. This effect might rely on an altered glutamatergic transmission, as synaptic expression of NMDAR subunit GluN2B is reduced in mice lacking IL-17A. At the same time, exposure to high concentrations of IL-17A was found to impair LTP induction through modulation of NMDAR currents. These results suggest a dual effect of this cytokine on striatal synaptic plasticity, showing the IL-17 axis as a key neuromodulator of the BG circuit, with potential implications in the pathogenesis of neuroinflammatory and neuropsychiatric disorders.
基底神经节（BG）网络在整合皮层输入方面发挥着关键作用，对运动学习、行为、情绪反应和认知功能至关重要。关于免疫细胞和可溶性免疫介质如何影响BG活动，目前知之甚少。白细胞介素-17A（IL-17A）因其在生理和病理条件下作为皮层突触传递和可塑性的神经调节剂的新作用而备受关注。然而，其在诸如BG回路等皮层下结构水平上的作用仍不清楚。在本研究中，我们证明纹状体中型多棘神经元（MSN）高度表达IL-17RA，并且IL-17轴有助于这些细胞中突触可塑性的生理表达。事实上，在缺乏IL-17A或IL-17RA的小鼠中，长时程增强（LTP）诱导显著降低。这种效应可能依赖于谷氨酸能传递的改变，因为在缺乏IL-17A的小鼠中，NMDAR亚基GluN2B的突触表达减少。同时，发现暴露于高浓度的IL-17A会通过调节NMDAR电流损害LTP诱导。这些结果表明这种细胞因子对纹状体突触可塑性具有双重作用，表明IL-17轴是BG回路的关键神经调节剂，对神经炎症和神经精神疾病的发病机制具有潜在影响。
