Le Anh Duc, Fu Marissa, Carper Ashley, Zegarowicz Elizabeth, Kumar Riya, Zacharias Gloria, Garcia A Denise R
Departments of Biology, Drexel University, Philadelphia, Pennsylvania 19104.
Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129
J Neurosci. 2025 Mar 12;45(11):e1336242025. doi: 10.1523/JNEUROSCI.1336-24.2025.
The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which neural activity is coupled to gene expression are not well understood. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte-derived molecules that modify synapses. Whisker stimulation in both male and female mice promotes activity-dependent Shh signaling selectively in the somatosensory, but not in the visual cortex, whereas sensory deprivation reduces Shh activity, demonstrating bidirectional regulation of the pathway by sensory experience. Selective loss of Shh signaling in astrocytes reduces expression of Hevin and SPARC and occludes activity-dependent synaptic plasticity. Taken together, these data identify Shh signaling as an activity-dependent, molecular signaling pathway that regulates astrocyte gene expression and promotes astrocyte modulation of synaptic plasticity.
神经活动对星形胶质细胞的影响以及它们与神经元的相互作用已成为突触功能的重要调节因子。星形胶质细胞表现出基因表达的活动依赖性变化，然而神经活动与基因表达耦合的分子机制尚未完全清楚。分子信号通路——音猬因子（Shh）介导神经元与星形胶质细胞的通信并调节皮质突触的组织。在这里，我们证明神经活动刺激皮质星形胶质细胞中的Shh信号传导，并上调Hevin和SPARC的表达，这两种星形胶质细胞衍生的分子可修饰突触。对雄性和雌性小鼠的触须刺激在体感皮层而非视觉皮层中选择性地促进了活动依赖性Shh信号传导，而感觉剥夺则降低了Shh活性，这表明该通路受感觉经验的双向调节。星形胶质细胞中Shh信号的选择性缺失会降低Hevin和SPARC的表达，并阻碍活动依赖性突触可塑性。综上所述，这些数据确定Shh信号传导是一种活动依赖性的分子信号通路，可调节星形胶质细胞基因表达并促进星形胶质细胞对突触可塑性的调节。
