Research Paper|Volume 12, Issue 7|pp 6324—6339

Anterior thalamic nucleus stimulation protects hippocampal neurons by activating autophagy in epileptic monkeys

Ting-Ting Du¹, Guanyu Zhu², Yingchuan Chen², Lin Shi², Defeng Liu², Yuye Liu², Xin Zhang¹, Jianguo Zhang^1,^2,³

¹Department of Functional Neurosurgery, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China
²Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
³Beijing Key Laboratory of Neurostimulation, Beijing 100070, China

* Equal contribution

Received: December 20, 2019Accepted: February 5, 2020Published: April 8, 2020

Copyright © 2020 Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is effective in treating temporal lobe epilepsy (TLE) and protects hippocampal neurons. Autophagy plays an essential role in epileptogenesis; however, the underlying effect of autophagy on ANT-DBS-mediated neuroprotection remains unclear. A monkey model of epilepsy was established by injecting kainic acid into the hippocampus and amygdala using a robot-assisted system. ANT-DBS was delivered in the chronic stage of the epileptic model and continued for 8 weeks. We found that ANT-DBS reduced the frequency of seizures and exerted neuroprotective effects via activating autophagy in hippocampal neurons. ANT-DBS increased light chain 3 (LC3) II level and co-localization of LC3 and lysosomal-associated membrane protein-1, accompanied by decreased expression of the autophagy substrate ubiquitin-binding protein p62, suggesting increased autophagosome formation. Most importantly, brain-derived neurotrophic factor (BDNF) –tropomyosin-related kinase type B (TrkB) pathway were involved in the regulation of autophagy. Both protein levels were reduced by ANT-DBS, and there was less phosphorylation of downstream regulators, extracellular signal-regulated kinase and Akt, followed by inactivation of mammalian target of rapamycin complex 1. Taken together, chronic ANT-DBS exerts neuroprotective effects on hippocampal neurons through inducing autophagy via suppressing the BDNF–TrkB pathway in a TLE monkey model.