Data_Sheet_1_Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.PDF

Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.

携带AMPA受体GluA1亚基缺陷的基因靶向小鼠（Gria1-/- mice）在新颖环境中表现出显著的运动过度表型，提示该模型可作为躁狂症、精神分裂症及注意缺陷多动障碍等多动障碍类疾病的研究模型。该行为异常与海马神经元激活增强密切相关，且可通过锂盐、丙戊酸、拉莫三嗪等抗躁狂药物的慢性给药干预得到缓解。本研究发现，全身性给予大麻二酚（cannabidiol）可显著削弱Gria1-/-小鼠的运动过度症状及海马组织的c-Fos表达水平，且对野生型同窝对照小鼠无显著影响。急性双侧海马背侧输注大麻二酚可部分阻断Gria1-/-小鼠的运动过度表现，但对野生型小鼠的自主活动无作用。通过氯氮平-N-氧化物（clozapine-N-oxide）激活背侧海马的抑制性DREADD受体hM4Gi（inhibitory DREADD receptor hM4Gi），可强力抑制Gria1-/-小鼠的运动过度，却不影响野生型小鼠的自主活动。本研究结果表明，海马神经元兴奋性增强与GluA1亚基缺陷小鼠显著的新颖环境诱导性运动过度直接相关。当通过药物治疗或化学遗传学抑制手段在海马区特异性降低神经元对新颖刺激的过度应答时，Gria1-/-小鼠的行为多动症状可得到改善，这提示多动行为相关的海马功能障碍可通过大麻二酚进行靶向治疗。