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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00302

A purinergic P2 receptor family-mediated increase in thrombospondin-1 bolsters synaptic density and epileptic seizure activity in the amygdala-kindling rat model

  • 1School of Pharmaceutical Sciences, Binzhou Medical University, China
  • 2Shandong Academy of Medical Sciences (SDAMS), China

Previous studies suggest that the thrombospondin-1/transforming growth factor-β1 (TSP-1/TGF-β1) pathway may be critical in synaptogenesis during development, and that the purinergic P2 receptor family could regulate synaptogenesis by modulating TSP-1 signaling. However, it is unclear whether this pathway plays a role in synaptogenesis during epileptic progression. This study was designed to investigate this question by analyzing the dynamic changes and effects of TSP-1 levels on the density of synaptic markers related to epileptic seizure activity. In addition, we evaluated whether P2-type receptors could regulate these effects. We generated a rat seizure model via amygdala kindling, and inhibited TSP-1 activity using siRNA interference and pharmacological inhibition. We treated the rats with antagonists of P2 or P2Y receptors, PPADS or Reactive Blue 2. Following this, we quantified TSP-1 and TGF-β1 immunoreactivity, the density of synaptic markers, and seizure activity. There were significantly more synapses/excitatory synapses in several brain regions, such as the hippocampus, which were associated with progressing epileptic discharges after kindling. These were associated with increased TSP-1 and TGF-β1 immunoreactivity. Genetic or pharmacologic inhibition of TSP-1 significantly reduced the density of synaptic/excitatory synaptic markers and inhibited the generalization of focal epilepsy. The administration of PPADS or Reactive Blue 2 attenuated the increase in TSP-1 immunoreactivity and the density of synaptic markers following kindling, and abolished most epileptic seizure activity. Taken together, our results indicate that the TSP-1/TGF-β1 pathway and its regulation by P2, particularly P2Y-type receptors, may be a critical promoter of synaptogenesis during the progression of epilepsy. Therefore, components of this pathway may be targets for novel anti-epileptic drug development.

Keywords: Epileptogenesis, astrocyte, synapse, thrombospondin-1, purinergic receptor 2

Received: 11 Apr 2018; Accepted: 20 Aug 2018.

Edited by:

Carl E. Stafstrom, Johns Hopkins Medicine, United States

Reviewed by:

Rodrigo A. Cunha, Faculdade de Medicina, Universidade de Coimbra, Portugal
Ji Won Um, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea  

Copyright: © 2018 Sun, Ma, Zhang, Pan, Wang, Zhang, Zhang, Wang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Wei Zhu, Shandong Academy of Medical Sciences (SDAMS), Jinan, 250062, Shandong, China,