Pais Mariana Lapo, Sereno José, Tomé Vanessa A, Fonseca Carla, Seco Camila, Ribeiro Inês, Martins João, Fortuna Ana, Abrunhosa Antero, Pinto Luísa, Castelo-Branco Miguel, Gonçalves Joana
University of Coimbra, Faculty of Sciences and Technology, Coimbra, Portugal.
University of Coimbra, Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal.
Transl Psychiatry. 2025 Jul 21;15(1):251. doi: 10.1038/s41398-025-03464-7.
Social behavior is highly sensitive to brain network dysfunction caused by neuropsychiatric conditions like autism spectrum disorders (ASDs). Some studies suggest that autistic females show fewer social skill impairments than autistic males. However, the relationship between sex differences in social behavior and sexually dimorphic brain neurophysiology in ASD remains unclear. We hypothesize that sex-specific changes in cortical neurophysiology drive the sexual dimorphism observed in social behavior for ASD. To test this, we used male and female Tsc2 mice, a genetic ASD model, to examine cortical neuron morphology, the serotonergic system, E/I balance, structural connectivity, and social behavior. At the cellular level, transgenic males had shorter and less complex cortical basal dendrites, while transgenic females showed the opposite in apical dendrites. Notably, only Tsc2 females exhibited changes in the serotonergic system and E/I balance, with reduced cortical 5-HT receptor density and increased excitability. Additionally, activation of these serotonin receptors in transgenic animals correlated with E/I imbalance, highlighting inherent sexual dimorphisms in neuronal connectivity. In parallel, the TSC2 mouse model displayed sex-dependent changes in the structural connectivity of the cortex-amygdala-hippocampus circuit and social behavior: females showed a reduced number of axonal fiber pathways and reduced sociability, while males exhibited a loss of tissue density and deficits in social novelty. Moreover, in our ASD mouse model, better social performance correlated with the cortical serotonergic system. Our findings suggest that sex-dependent alterations in cortical neurophysiology, particularly in the serotonergic system, may contribute to the sexually dimorphic social behaviors observed in ASD.
社会行为对由自闭症谱系障碍（ASD）等神经精神疾病引起的脑网络功能障碍高度敏感。一些研究表明，自闭症女性表现出的社交技能损害比自闭症男性少。然而，ASD中社会行为的性别差异与大脑神经生理学性别二态性之间的关系仍不清楚。我们假设，皮质神经生理学的性别特异性变化驱动了ASD社会行为中观察到的性别二态性。为了验证这一点，我们使用了雄性和雌性Tsc2小鼠（一种遗传性ASD模型）来检查皮质神经元形态、血清素能系统、兴奋/抑制（E/I）平衡、结构连接性和社会行为。在细胞水平上，转基因雄性小鼠的皮质基底树突较短且不太复杂，而转基因雌性小鼠的顶端树突则相反。值得注意的是，只有Tsc2雌性小鼠的血清素能系统和E/I平衡发生了变化，皮质5-羟色胺受体密度降低，兴奋性增加。此外，转基因动物中这些血清素受体的激活与E/I失衡相关，突出了神经元连接中固有的性别二态性。同时，TSC2小鼠模型在皮质-杏仁核-海马回路的结构连接性和社会行为方面表现出性别依赖性变化：雌性小鼠的轴突纤维通路数量减少，社交能力降低，而雄性小鼠则表现出组织密度丧失和对社会新奇性的缺陷。此外，在我们的ASD小鼠模型中，更好的社会行为表现与皮质血清素能系统相关。我们的研究结果表明，皮质神经生理学的性别依赖性改变，特别是血清素能系统的改变，可能导致了ASD中观察到的性别二态性社会行为。
