Institute for Applied Physiology, Ulm University, Ulm, Germany.
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Transl Psychiatry. 2018 Oct 9;8(1):212. doi: 10.1038/s41398-018-0268-6.
Elevated activity at the output stage of the anterior hippocampus has been described as a physiological endophenotype of schizophrenia, and its development maps onto the transition from the prodromal to the psychotic state. Interventions that halt the spreading glutamatergic over-activity in this region and thereby the development of overt schizophrenia could be promising therapies. However, animal models with high construct validity to support such pre-clinical development are scarce. The Cyclin-D2 knockout (CD2-KO) mouse model shows a hippocampal parvalbumin-interneuron dysfunction, and its pattern of hippocampal over-activity shares similarities with that seen in prodromal patients. Conducting a comprehensive phenotyping of CD2-KO mice, we found that they displayed novelty-induced hyperlocomotion (a rodent correlate of positive symptoms of schizophrenia), that was largely resistant against D1- and D2-dopamine-receptor antagonism, but responsive to the mGluR2/3-agonist LY379268. In the negative symptom domain, CD2-KO mice showed transiently reduced sucrose-preference (anhedonia), but enhanced interaction with novel mice and objects, as well as normal nest building and incentive motivation. Also, unconditioned anxiety, perseveration, and motor-impulsivity were unaltered. However, in the cognitive domain, CD2-knockouts showed reduced executive function in assays of rule-shift and rule-reversal learning, and also an impairment in working memory, that was resistant against LY379268-treatment. In contrast, sustained attention and forms of spatial and object-related memory that are mediated by short-term habituation of stimulus-specific attention were intact. Our results suggest that CD2-KO mice are a valuable model in translational research targeted at the pharmacoresistant cognitive symptom domain in causal relation to hippocampal over-activity in the prodrome-to-psychosis transition.
前海马回输出阶段活性升高被描述为精神分裂症的生理内表型，其发展与前驱期到精神病状态的转变相对应。能阻止该区域谷氨酸能过度活动扩散并从而阻止明显精神分裂症发展的干预措施可能是很有前途的治疗方法。然而，具有高构建效度以支持这种临床前开发的动物模型却很少。周期素 D2 敲除（CD2-KO）小鼠模型显示海马区 parvalbumin 中间神经元功能障碍，其海马区过度活动模式与前驱期患者所见相似。对 CD2-KO 小鼠进行全面表型分析，我们发现它们表现出新奇诱导的过度活跃（精神分裂症阳性症状的啮齿动物相关物），这种过度活跃在很大程度上对 D1 和 D2 多巴胺受体拮抗剂具有抗性，但对 mGluR2/3 激动剂 LY379268 有反应。在阴性症状领域，CD2-KO 小鼠表现出短暂的蔗糖偏好减少（快感缺失），但对新老鼠和物体的互动增强，以及正常筑巢和激励动机。此外，非条件性焦虑、持续坚持和运动冲动性没有改变。然而，在认知领域，CD2 敲除小鼠在规则转换和规则反转学习的测验中表现出执行功能下降，并且工作记忆也受损，而 LY379268 治疗对其没有作用。相比之下，执行功能、持续注意力以及由刺激特异性注意力的短期习惯化介导的空间和物体相关记忆形式仍然完整。我们的研究结果表明，CD2-KO 小鼠是一种有价值的模型，可用于针对前驱期到精神病发作过渡中与海马过度活动有关的、具有抗药性的认知症状领域的转化研究。
