Kudo Takehiro, Takuwa Hiroyuki, Takahashi Manami, Urushihata Takuya, Shimojo Masafumi, Sampei Kazuaki, Yamanaka Mitsugu, Tomita Yutaka, Sahara Naruhiko, Suhara Tetsuya, Higuchi Makoto
Sumitomo Pharma Co., Ltd., Osaka, Japan.
Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
iScience. 2023 Mar 5;26(4):106342. doi: 10.1016/j.isci.2023.106342. eCollection 2023 Apr 21.
In Alzheimer's disease (AD), network hyperexcitability is frequently observed and associated with subsequent cognitive impairment. Dysfunction of inhibitory interneurons (INs) is thought to be one of the key biological mechanisms of hyperexcitability. However, it is still unknown how INs are functionally affected in tau pathology, which is a major pathology in AD. To clarify this, we evaluated the neuronal activity of cortical INs in 6-month-old rTg4510 mice, a model of tauopathy. Calcium imaging with mDlx enhancer-driven labeling revealed that neuronal activity in INs was decreased in rTg4510 mice. In the patch clamp recording, the firing properties of fast-spiking INs were altered so as to reduce their activity in rTg4510 mice. In parallel with microglial activation, perineuronal nets around parvalbumin-positive INs were partially disrupted in rTg4510 mice. Taken together, our data indicate that the excitability of cortical fast-spiking INs is decreased, possibly because of the disruption of perineuronal nets.
在阿尔茨海默病（AD）中，经常观察到网络兴奋性过高，并与随后的认知障碍相关。抑制性中间神经元（INs）功能障碍被认为是兴奋性过高的关键生物学机制之一。然而，在AD的主要病理学——tau病理学中，INs在功能上如何受到影响仍不清楚。为了阐明这一点，我们评估了6月龄rTg4510小鼠（一种tau病变模型）皮质INs的神经元活动。利用mDlx增强子驱动标记的钙成像显示，rTg4510小鼠INs中的神经元活动降低。在膜片钳记录中，快速放电INs的放电特性发生改变，从而降低了rTg4510小鼠中它们的活动。与小胶质细胞激活同时发生的是，rTg4510小鼠中微小清蛋白阳性INs周围的神经周网部分被破坏。综上所述，我们的数据表明皮质快速放电INs的兴奋性降低，可能是由于神经周网的破坏。
