Steffen Johannes, Deshpande Divija, Düsedau Henning Peter, Schmitz Janna, Figueiredo Caio Andreeta, Velleman Laura, Pitzer Claudia, Klose Christoph S N, Dunay Ildiko R
Institute of Inflammation and Neurodegeneration, Otto-Von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany.
Department of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
J Neuroinflammation. 2025 Jun 23;22(1):163. doi: 10.1186/s12974-025-03485-5.
The immune system provides multiple layers of protection that extend beyond conventional pathogen defense, including context-dependent modulation of behavior. However, the mechanisms driving these immune-mediated behavioral modifications remain incompletely understood. Here, we demonstrate that group 2 innate lymphoid cells (ILC2s) shape hippocampal synaptic development during early postnatal stages, with lasting effects on adult behavior, learning, and memory.Using flow synaptometry, we identified a selective reduction in hippocampal VGAT GABAergic/glycinergic inhibitory synapse frequency at postnatal day 15 in ILC2-deficient mice, while the proportions of inhibitory GABAergic (NL2) or excitatory glutamatergic (GluR1) synapses remained unaltered. These synaptic changes occurred without detectable phenotypical changes in cortical and hippocampal microglia. In adulthood, ILC2-deficient mice displayed significant impairments in hippocampus-dependent tasks, such as active place avoidance and operant conditioning, reflecting deficits in learning and memory.Our findings reveal a critical role for ILC2s in the formation of inhibitory synapses in the hippocampus, highlighting the impact of immune signaling on neuronal network maturation during a crucial period of brain development. This early immune-mediated modulation may have lasting effects on neuronal circuitry and cognitive functions that persist into adulthood, emphasizing the long-term implications of neuro-immune interactions for normal cognitive development and function.
免疫系统提供了多层次的保护，其作用超出了传统的病原体防御范畴，包括对行为的情境依赖性调节。然而，驱动这些免疫介导的行为改变的机制仍未完全清楚。在此，我们证明2型固有淋巴细胞（ILC2s）在出生后早期塑造海马体突触发育，并对成年后的行为、学习和记忆产生持久影响。利用流式突触计量法，我们发现ILC2缺陷小鼠在出生后第15天海马体VGAT GABA能/甘氨酸能抑制性突触频率有选择性降低，而抑制性GABA能（NL2）或兴奋性谷氨酸能（GluR1）突触的比例保持不变。这些突触变化发生时，皮质和海马体小胶质细胞没有可检测到的表型变化。在成年期，ILC2缺陷小鼠在依赖海马体的任务中表现出显著损伤，如主动位置回避和操作性条件反射，反映出学习和记忆方面的缺陷。我们的研究结果揭示了ILC2s在海马体抑制性突触形成中的关键作用，突出了免疫信号在大脑发育关键时期对神经网络成熟的影响。这种早期免疫介导的调节可能对持续到成年期的神经元回路和认知功能产生持久影响，强调了神经免疫相互作用对正常认知发育和功能的长期影响。
