Pathological forms of the microtubule-associated protein tau are involved in a large group of neurodegenerative diseases named tauopathies, including frontotemporal lobar degeneration (FTLD-tau). K369I mutant tau transgenic mice (K3 mice) recapitulate neural and behavioural symptoms of FTLD, including tau aggregates in the cortex, alterations to nigrostriatum, memory deficits and parkinsonism. The aim of this study was to further characterise the K3 mouse model by examining functional alterations to the striatum. Whole-cell patch-clamp electrophysiology was used to investigate the properties of striatal neurons in K3 mice and wildtype controls. Additionally, striatal-based instrumental learning tasks were conducted to assess goal-directed versus habitual behaviours (i.e., by examining sensitivity to outcome devaluation and progressive ratios). The K3 model demonstrated significant alterations in the discharge properties of striatal neurons relative to wildtype mice, which manifested as a shift in neuronal output towards a burst firing state. K3 mice acquired goal-directed responding faster than control mice and were goal-directed at test unlike wildtype mice, which is likely to indicate reduced capacity to develop habitual behaviour. The observed pattern of behaviour in K3 mice is suggestive of deficits in dorsal lateral striatal function and this was supported by our electrophysiological findings. Thus, both the electrophysiological and behavioural alterations indicate that K3 mice have early deficits in striatal function. This finding adds to the growing literature which indicate that the striatum is impacted in tau-related neuropathies such as FTLD, and further suggests that the K3 model is a unique mouse model for investigating FTLD especially with striatal involvement.

微管相关蛋白tau的病理形式与一大批称为tauopathies的神经退行性疾病有关，包括额颞叶变性（FTLD-tau）。K369I突变tau转基因小鼠（K3小鼠）概括了FTLD的神经和行为症状，包括皮层中的tau聚集，黑质纹状体改变，记忆力减退和帕金森病。这项研究的目的是通过检查纹状体的功能改变来进一步表征K3小鼠模型。使用全细胞膜片钳电生理研究K3小鼠和野生型中纹状体神经元的特性控制。此外，进行了基于纹状体的工具学习任务，以评估目标导向与习惯行为之间的关系（即，通过检查对结果贬值和进步比率的敏感性）。相对于野生型小鼠，K3模型显示出纹状体神经元放电特性的显着改变，表现为神经元输出朝着爆发状态的转变。与野生型小鼠相比，K3小鼠获得的目标导向反应速度快于对照小鼠，并且在测试中具有目标导向作用小鼠，这可能表明其减少了习惯性行为的能力。在K3小鼠中观察到的行为模式提示背侧纹状体功能缺陷，这得到了我们的电生理结果的支持。因此，电生理和行为改变都表明K3小鼠的纹状体功能有早期缺陷。这一发现增加了越来越多的文献，这些文献表明纹状体受到与tau相关的神经病变（如FTLD）的影响，并且进一步表明K3模型是用于研究FTLD（尤其是纹状体受累）的独特小鼠模型。