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Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model

Acta Pharmacologica Sinica volume 44, pages 2376–2387 (2023)Cite this article

Abstract

Cognitive deficit is a common comorbidity in temporal lobe epilepsy (TLE) and is not well controlled by current therapeutics. How epileptic seizure affects cognitive performance remains largely unclear. In this study we investigated the role of subicular seizure-activated neurons in cognitive impairment in TLE. A bipolar electrode was implanted into hippocampal CA3 in male mice for kindling stimulation and EEG recording; a special promoter with enhanced synaptic activity-responsive element (E-SARE) was used to label seizure-activated neurons in the subiculum; the activity of subicular seizure-activated neurons was manipulated using chemogenetic approach; cognitive function was assessed in object location memory (OLM) and novel object recognition (NOR) tasks. We showed that chemogenetic inhibition of subicular seizure-activated neurons (mainly CaMKIIα+ glutamatergic neurons) alleviated seizure generalization and improved cognitive performance, but inhibition of seizure-activated GABAergic interneurons had no effect on seizure and cognition. For comparison, inhibition of the whole subicular CaMKIIα+ neuron impaired cognitive function in naïve mice in basal condition. Notably, chemogenetic inhibition of subicular seizure-activated neurons enhanced the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks. Our results demonstrate that subicular seizure-activated neurons contribute to cognitive impairment in TLE, suggesting seizure-activated neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

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Fig. 1: Chemogenetic inhibition of subicular seizure-activated neurons alleviates seizure generalization.
Fig. 2: Inhibition of subicular seizure-activated neurons rescues cognitive deficit in epileptic mice.
Fig. 3: Chemogenetic inhibition of whole subicular CaMKIIα+ neuron impairs cognitive function in naïve mice.
Fig. 4: Inhibition of subicular seizure-activated neurons enhances recruitment of cognition task-responsive c-fos+ neurons.
Fig. 5: Inhibition of subicular seizure-activated neurons enhances neural activity during cognition tasks.

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Acknowledgements

This project was supported by grants from the National Key R&D Program of China (2021ZD0202803 and 2020YFA0803902), the National Natural Science Foundation of China (82022071), and the Natural Science Foundation of Zhejiang Province (LD22H310003).

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  1. These authors contributed equally: Lin Yang, Qi Zhang, Xue-qing Wu

Authors and Affiliations

  1. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Lin Yang, Qi Zhang, Xue-qing Wu, Xiao-yun Qiu, Fan Fei, Yu-yi Zheng, Meng-di Zhang, Qing-yang Zhang, Yu Wang, Fei Wang, Ceng-lin Xu, Ye-ping Ruan, Yi Wang & Zhong Chen

  2. Zhejiang Rehabilitation Medical Center, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310013, China

    Fan Fei & Yi Wang

  3. Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Nan-xi Lai, Yi Wang & Zhong Chen

  4. Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

    Zhong Chen

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Contributions

ZC, LY, and YW, contributed to conception and design of the study. LY, QZ, XQW, XYQ, FF, NXL, YYZ, QYZ, MDZ, YW, FW, CLX, and YPR contributed to acquisition and analysis of data. LY, YW, and ZC contributed to drafting the manuscript and figures.

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Correspondence to Yi Wang or Zhong Chen.

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Yang, L., Zhang, Q., Wu, Xq. et al. Chemogenetic inhibition of subicular seizure-activated neurons alleviates cognitive deficit in male mouse epilepsy model. Acta Pharmacol Sin 44, 2376–2387 (2023). https://doi.org/10.1038/s41401-023-01129-z

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