tau 病理学导致 GABA 能中间神经元丧失，导致突触可塑性改变和行为障碍。

Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments.

机构信息

Department of Physiology & Neuroscience, New York University School of Medicine, 550 First Ave, SRB 610, New York, NY 10016, USA.

出版信息

Acta Neuropathol Commun. 2013 Jul 11;1:34. doi: 10.1186/2051-5960-1-34.

DOI:10.1186/2051-5960-1-34

PMID:24252661

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3893396/

Abstract

BACKGROUND

Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs.

RESULTS

We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice.

CONCLUSIONS

We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies.

摘要

背景

Tau 是一种微管稳定蛋白，主要在神经元中表达。Tau 聚集形成寡聚物和缠结被认为是 Tau 病的重要病理事件，如额颞叶痴呆（FTD）和阿尔茨海默病（AD）。Tau 病也与突触可塑性缺陷有关，如长时程增强（LTP），但 Tau 在这些缺陷表现中的具体作用还不是很清楚。我们检查了在表达某些遗传性 FTD 中鉴定出的突变 Tau 的 JNPL3（BL6）小鼠中持久的突触可塑性形式。

结果

我们发现，年龄较大（>12 个月）的 JNPL3（BL6）小鼠表现出增强的海马体晚期（L-LTP），而年轻的 JNPL3（BL6）小鼠（6 个月大）表现出正常的 L-LTP。年龄较大的 JNPL3（BL6）小鼠中的这种增强的 L-LTP 可以用 GABAAR 激动剂唑吡坦挽救，表明 GABA 能功能丧失。事实上，我们发现突变小鼠显示海马 GABA 能中间神经元减少。最后，我们还发现突变 Tau 的表达导致年龄较大的 JNPL3（BL6）小鼠出现严重的感觉运动门控和海马体依赖性记忆缺陷。