Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model

Takehiro Kudo; Hiroyuki Takuwa; Manami Takahashi; Takuya Urushihata; Masafumi Shimojo; Kazuaki Sampei; Mitsugu Yamanaka; Yutaka Tomita; Naruhiko Sahara; Tetsuya Suhara; Makoto Higuchi

doi:10.1016/j.isci.2023.106342

Selective dysfunction of fast-spiking inhibitory interneurons and disruption of perineuronal nets in a tauopathy mouse model

iScience. 2023 Mar 5;26(4):106342. doi: 10.1016/j.isci.2023.106342. eCollection 2023 Apr 21.

Authors

Takehiro Kudo^{1

2

3}, Hiroyuki Takuwa^{2

4}, Manami Takahashi^{2

4}, Takuya Urushihata², Masafumi Shimojo², Kazuaki Sampei¹, Mitsugu Yamanaka¹, Yutaka Tomita⁵, Naruhiko Sahara², Tetsuya Suhara^{2

4}, Makoto Higuchi²

Affiliations

¹ Sumitomo Pharma Co., Ltd., Osaka, Japan.
² Department of Functional Brain Imaging, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
³ Collaborative Chairs Quantum Life Science·and Molecular Imaging, Tohoku University, Sendai, Japan.
⁴ Department of Neuromapping and Neuromodulation Group, Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
⁵ Department of Neurology, Keio University School of Medicine, Tokyo, Japan.

Abstract

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.

Keywords: Cellular neuroscience; Molecular neuroscience.