Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
Folia Neuropathol. 2022;60(4):390-402. doi: 10.5114/fn.2022.123999.
Purinergic signalling is involved in the control of several processes related to brain development, such as neurogenesis and gliogenesis, migration and differentiation of neuronal precursors, synaptogenesis and synaptic elimination to achieve a fully wired and efficient mature brain. Therefore, any deregulation of purine-dependent signalling mediated by stimulation of specific adenosine and purinergic receptor subtypes: P1, P2X, or P2Y, can lead to functional deficits and the development of neuropsychiatric disorders, including autism spectrum disorders (ASD). In this study, we investigated the changes in expression and activity of selected purinergic receptors during rat brain development in an animal model of ASD. Pregnant dams received an intraperitoneal injection of valproic acid (VPA; 450 mg/kg body weight) at embryonic day (ED) 12.5, around the time of neural tube closure. Subsequently, changes in the expression and activity of specific purinergic receptor subtypes were analysed at ED19, an important prenatal stage of brain development. Our results suggest that prenatal VPA exposure leads to a significant increase in the level and activity of adenosinergic receptors A1, A2b and A3, which are involved in the regulation of progenitor cell proliferation and nerve growth, and upregulation of purinergic P2X2/P2X3 receptors, which in turn may contribute to the postnatal neuroanatomical abnormalities and synaptic dysfunction. Conversely, the significant downregulation of P2Y1 and P2X7 receptors, together with their reduced activity in the embryonic VPA brain, may indicate disturbances in the processes of neuronal precursor migration and differentiation, dendritic and axonal formation, and glutamate/GABA imbalance, thereby altering neuronal excitability. In conclusion, defects in purinergic signalling induced by prenatal VPA exposure could have a profound impact on brain development during embryogenesis and on intellectual and behavioural functions after birth. These observations could provide clues for future implementation of potential therapeutic strategies for ASD.
嘌呤能信号参与了许多与大脑发育相关的过程的控制，如神经发生和神经胶质发生、神经元前体的迁移和分化、突触形成和突触消除，以实现完全连接和高效成熟的大脑。因此，任何嘌呤依赖信号的调节紊乱，通过刺激特定的腺苷和嘌呤能受体亚型：P1、P2X 或 P2Y，都可能导致功能缺陷和神经精神疾病的发展，包括自闭症谱系障碍（ASD）。在这项研究中，我们在 ASD 的动物模型中研究了选定嘌呤能受体在大鼠大脑发育过程中的表达和活性变化。怀孕的母鼠在胚胎期（ED）12.5 时，即神经管闭合时，接受了腹腔注射丙戊酸（VPA；450mg/kg 体重）。随后，在大脑发育的重要产前阶段 ED19 分析了特定嘌呤能受体亚型的表达和活性变化。我们的结果表明，产前 VPA 暴露导致腺苷能受体 A1、A2b 和 A3 的水平和活性显著增加，这些受体参与了祖细胞增殖和神经生长的调节，以及嘌呤能 P2X2/P2X3 受体的上调，这反过来可能导致产后神经解剖异常和突触功能障碍。相反，P2Y1 和 P2X7 受体的显著下调，以及它们在胚胎 VPA 大脑中的活性降低，可能表明神经元前体迁移和分化、树突和轴突形成以及谷氨酸/GABA 失衡的过程受到干扰，从而改变神经元兴奋性。总之，产前 VPA 暴露引起的嘌呤能信号缺陷可能对胚胎发生期间的大脑发育以及出生后的智力和行为功能产生深远影响。这些观察结果可能为未来实施 ASD 的潜在治疗策略提供线索。
