Alterations of Cannabinoid Type 1 Receptor Inhibitory Interneuron Boutons in Mesial Temporal Lobe Epilepsy
Abstract number :
1.015
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2018
Submission ID :
501942
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Jia-Yi Wang, University of Pittsburgh; Ahmad Alhourani, University of Pittsburgh; Kenneth Fish, University of Pittsburgh; Thomas Wosny, University of Pittsburgh; and R. Mark Richardson, University of Pittsburgh
Rationale: Inhibitory interneurons exert powerful control over excitatory dentate granule neurons in the hippocampus. Alterations to these neurons are thought to play a key role in the pathogenesis of mesial temporal lobe epilepsy (MTLE). Specifically, a population of inhibitory neurons expressing cannabinoid type 1 receptors (CB1R) has been hypothesized to play a role in MTLE, although there are contradictory findings regarding CB1R-mediated anti-epileptic and pro-epileptic effects. Therefore, we aimed to characterize changes to inhibitory CB1R+ perisomatic terminal density and protein content at the synaptic level in the human epileptic dentate gyrus. Methods: We obtained 12 hippocampal samples from human subjects with medically refractory MTLE (6 sclerotic, 6 nonsclerotic) who underwent en bloc hippocampectomy as part of standard anterior temporal lobectomy surgery, and 6 age- and sex-matched healthy postmortem controls. We applied a multi-label, semi-quantitative fluorescence confocal microscopy method and an advanced post-imaging analysis paradigm to analyze the densities and relative protein levels of CB1R+ boutons in the granule cell layer of the human dentate gyrus. We used differential GAD isoform expression to identify inhibitory terminals and to evaluate potential subpopulations of CB1R+ neurons. Results: CB1R+ bouton densities were significantly altered in MTLE. Namely, CB1R+ bouton density was decreased specifically in sclerotic samples compared to controls. In identified inhibitory CB1R+ boutons, downregulation of GAD protein was observed in sclerotic and nonsclerotic samples compared to controls. Conclusions: We demonstrate CB1R containing interneuron-subtype specific epilepsy-related changes at the synaptic bouton level in human MTLE, further advancing our understanding of the disease state in human MTLE particularly as it relates to the effect on endocannabinoid signaling. These findings may help develop better pharmacotherapies for medically resistant MTLE. Funding: Clinical Scientist Training Program at the University of Pittsburgh School of Medicine (JW), Walter L. Copeland Fund of the Pittsburgh Foundation (RMR and JW), Grant UL1 TR0000005 from the National Center for Advancing Translational Sciences (RMR and KNF)