A Purinergic P2 Receptor Family-Mediated Increase in Thrombospondin-1 Bolsters Synaptic Density and Epileptic Seizure Activity in the Amygdala-Kindling Rat Model

Sun, Hongliu and Ma, Luyu and Zhang, Yurong and Pan, Xiaohong and Wang, Chaoyun and Zhang, Jinjin and Zhang, Xiuli and Sun, Hongwei and Wang, Qiaoyun and Zhu, Wei (2018) A Purinergic P2 Receptor Family-Mediated Increase in Thrombospondin-1 Bolsters Synaptic Density and Epileptic Seizure Activity in the Amygdala-Kindling Rat Model. Frontiers in Cellular Neuroscience, 12. ISSN 1662-5102

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Abstract

Previous studies suggested that the thrombospondin-1/transforming growth factor-β1 (TSP-1/TGF-β1) pathway might 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 that are 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 small interfering RNA (siRNA) interference and pharmacological inhibition. We treated the rats with antagonists of P2 or P2Y receptors, pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic (PPADS) or Reactive Blue 2. Following this, we quantified TSP-1 and TGF-β1 immunoreactivity (IR), 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-IR. 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-IR and the increase in the density of synaptic markers that follows kindling and abolished most of the epileptic seizure activity. Altogether, 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 antiepileptic drug development.

Item Type: Article
Subjects: Impact Archive > Medical Science
Depositing User: Managing Editor
Date Deposited: 30 May 2023 11:12
Last Modified: 19 Jan 2024 10:59
URI: http://research.sdpublishers.net/id/eprint/2389

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