Normandie Univ, UNICAEN, INSERM U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @ Caen-Normandie (BB@C), GIP Cyceron, 14000, Caen, France.
Université Paris-Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurodégénératives, 92265, Fontenay-aux-Roses, France.
Mol Psychiatry. 2022 Apr;27(4):2197-2205. doi: 10.1038/s41380-022-01455-4. Epub 2022 Feb 10.
Tissue plasminogen activator (tPA) is a serine protease expressed in several brain regions and reported to be involved in the control of emotional and cognitive functions. Nevertheless, little is known about the structure-function relationships of these tPA-dependent behaviors. Here, by using a new model of constitutive tPA-deficient mice (tPA), we first show that tPA controls locomotor activity, spatial cognition and anxiety. To investigate the brain structures involved in these tPA-dependent behavioral phenotypes, we next generated tPA mice allowing conditional tPA deletion (cKO) following stereotaxic injections of adeno-associated virus driving Cre-recombinase expression (AAV-Cre-GFP). We demonstrate that tPA removal in the dentate gyrus of the hippocampus induces hyperactivity and partial spatial memory deficits. Moreover, the deletion of tPA in the central nucleus of the amygdala, but not in the basolateral nucleus, induces hyperactivity and reduced anxiety-like level. Importantly, we prove that these behaviors depend on the tPA present in the adult brain and not on neurodevelopmental disorders. Also, interestingly, our data show that tPA from Protein kinase-C delta-positive (PKCδ) GABAergic interneurons of the lateral/ capsular part of adult mouse central amygdala controls emotional functions through neuronal activation of the medial central amygdala. Together, our study brings new data about the critical central role of tPA in behavioral modulations in adult mice.
组织型纤溶酶原激活物（tPA）是一种在多个脑区表达的丝氨酸蛋白酶，据报道其参与了情绪和认知功能的控制。然而，对于这些依赖 tPA 的行为的结构-功能关系知之甚少。在这里，我们使用一种新的组成型 tPA 缺陷型小鼠（tPA）模型，首先表明 tPA 控制着运动活性、空间认知和焦虑。为了研究这些依赖 tPA 的行为表型所涉及的脑结构，我们接下来生成了允许在立体定位注射驱动 Cre 重组酶表达的腺相关病毒（AAV-Cre-GFP）后进行条件性 tPA 缺失（cKO）的 tPA 小鼠。我们证明，海马齿状回中 tPA 的去除会引起过度活跃和部分空间记忆缺陷。此外，杏仁核中央核中 tPA 的缺失，但不是基底外侧核中 tPA 的缺失，会引起过度活跃和焦虑样水平降低。重要的是，我们证明这些行为依赖于成年大脑中的 tPA，而不是神经发育障碍。此外，有趣的是，我们的数据表明，成年小鼠外侧/被囊部中央杏仁核中蛋白激酶 C 德尔塔阳性（PKCδ）GABA 能中间神经元中的 tPA 通过内侧中央杏仁核的神经元激活来控制情绪功能。总之，我们的研究为 tPA 在成年小鼠行为调节中的关键中枢作用提供了新的数据。
