Increased Excitability of the Hippocampal Dentate Gyrus in the IHKA Mouse Model for Temporal Lobe Epilepsy Can Be Suppressed by Activating the Adenosine A1 Receptor Signalling Pathway
Abstract number :
2.051
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2204380
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Simona Manzella, PhD Student – University of Ghent; Paul Boon, Professor – University of Ghent; Evelien Carrette, Professor – University of Ghent; Erine Craey, PhD student – University of Ghent; Jean Delbeke, Professor – University of Ghent; Lars Emil Larsen, Postdoc – University of Ghent; Robrecht Raedt, Professor – University of Ghent; Jeroen Spanoghe, PhD student – University of Ghent; Kristl Vonck, Professor – University of Ghent; Wytse Wadman, Professor – University of Ghent
Rationale: Activation of the adenosine A1 receptor (A1R) provides potent seizure suppression and its activation as a result of build-up of adenosine during seizures is believed to be an important endogenous mechanism for seizure termination. Unfortunately due to the side effects provoked by systemic administration, anti-epileptic treatments with adenosine A1R agonists are not available. In this study, we evaluated whether a novel photocaged A1R agonist could be used for light-triggered suppression of seizure focus hyperexcitability.
Methods: Dentate gyrus (DG) evoked potentials (EPs) were measured and compared in ex vivo hippocampal slices taken from control and epileptic intrahippocampal kainic acid mice to identify biomarkers of hyperexcitability. Next, epileptic hippocampal slices were incubated with 3µM of the coumarine-caged A1R agonist N6-cyclopentyladenosine (cagedCPA), which has a 7500-fold reduced affinity for the A1R receptor compared to its parent compound CPA but uncages to its active form by exposure to 405 nm light. Optical uncaging of cCPA was put under closed-loop control by triggering the 405 nm light flashes (25 ms, 4mW) by markers of increased DG excitability, to achieve stable reduction of hyperexcitability.
Results: We found that several parameter of DG evoked potentials were significantly increased in epileptic IHKA, including slope of the field excitatory postsynaptic potential (fEPSP, reflecting neurotransmission) as well as population spike amplitude (PS, reflecting postsynaptic activation). Closed-loop optical uncaging of cCPA, with PS amplitude as control variable, allowed to stably reduce PS amplitude and thus hyperexcitability of epileptic slices.
Conclusions: This study demonstrated increased evoked potentials reflecting hyperexcitability in the DG of the IHKA mouse model for TLE. It also confirmed that A1R signaling acts as potent suppressor of this hyperexcitability. Furthermore it provided proof-of-concept for a new closed-loop photopharmacology approach where an A1R agonist is uncaged via feedback-controlled light triggers to reduce the postsynaptic activation to a predefined target. We aim to further investigate the potential of photopharmacologically as targeted treatment for (temporal lobe) epilepsy.
Funding: FWO research project
Neurophysiology