Lo Shih-Ching, Wang Yuanyuan, Weber Martin, Larson Jessica L, Scearce-Levie Kimberly, Sheng Morgan
Departments of Neuroscience, and
Departments of Neuroscience, and.
J Neurosci. 2015 Feb 4;35(5):2118-32. doi: 10.1523/JNEUROSCI.3280-14.2015.
The ability to attend to relevant stimuli and to adapt dynamically as demands change is a core aspect of cognition, and one that is impaired in several neuropsychiatric diseases, including attention deficit/hyperactivity disorder. However, the cellular and molecular mechanisms underlying such cognitive adaptability are poorly understood. We found that deletion of the caspase-3 gene, encoding an apoptosis protease with newly discovered roles in neural plasticity, disrupts attention in mice while preserving multiple learning and memory capabilities. Attention-related deficits include distractibility, impulsivity, behavioral rigidity, and reduced habituation to novel stimuli. Excess exploratory activity in Casp3(-/-) mice was correlated with enhanced novelty-induced activity in the dentate gyrus, which may be related to our findings that caspase-3 is required for homeostatic synaptic plasticity in vitro and homeostatic expression of AMPA receptors in vivo in response to chronic or repeated stimuli. These results suggest an important role for caspase-3 in synaptic suppression of irrelevant stimuli.
关注相关刺激并随需求变化动态适应的能力是认知的核心方面，在包括注意力缺陷多动障碍在内的几种神经精神疾病中，这一能力会受损。然而，这种认知适应性背后的细胞和分子机制却知之甚少。我们发现，编码一种在神经可塑性中具有新发现作用的凋亡蛋白酶的半胱天冬酶-3基因的缺失，会扰乱小鼠的注意力，同时保留多种学习和记忆能力。与注意力相关的缺陷包括易分心、冲动、行为僵化以及对新刺激的习惯化减弱。Casp3(-/-)小鼠过度的探索活动与齿状回中由新奇感诱导的活动增强相关，这可能与我们的发现有关，即半胱天冬酶-3在体外稳态突触可塑性以及体内AMPA受体响应慢性或重复刺激的稳态表达中是必需的。这些结果表明半胱天冬酶-3在对无关刺激的突触抑制中起重要作用。
