Partial Agonist Activation of Trkb-r Prevents Interneuronal Abnormalities Following Neocortical Status Epilepticus
Abstract number :
1.148
Submission category :
2. Translational Research / 2E. Other
Year :
2022
Submission ID :
2204231
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:24 AM
Authors :
Maria Perez, PhD – Stanford University; Isabel Parada, BS – Stanford University; Tao Yang, PhD Senior Research Scientist – Stanford University; Paul Buckmaster, DVM, PhD Professor – Stanford University; Frank Longo, M.D., Ph.D. George E. and Lucy Becker Professor and Chair Department of Neurology and Neurological Sciences – Stanford University; David Prince, MD Edward F. and Irene Thiele Pimley Professor in Neurology and Neurological Sciences – Stanford University
This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session
Rationale: The mechanisms by which focal neocortical status epilepticus (FSE) induces chronic sequelae, including epileptogenesis, are not fully understood, and there are no available antiepileptogenic treatments. In other SE models, there are functional and structural abnormalities in interneuronal populations leading to a malfunction of the inhibitory system. The maintenance of interneurons is dependent on trophic support regulated by the activation of TrkB receptors (TrkB-Rs) by brain-derived neurotrophic factor. We hypothesized that a single episode of FSE induces abnormalities in inhibitory neurons and inhibitory synaptic connectivity and that treatment with a partial agonist of TrkB-Rs: PTX BD4-3 (BD, Adams et al., 2020) would rescue the observed abnormalities.
Methods: We induced a single episode of FSE by epidural application of gabazine and 4-AP (150µM) over the right somatosensory cortex of anesthetized mice (Perez-Ramirez et al., 2020). FSE was identified with EEG recordings and contralateral focal myoclonic activity. After ~2hr, seizures were terminated with an i.p. injection of diazepam (5-10 mg/kg). BD treatment (50 mg/kg/day) or vehicle was given via i.p. for 7 days, starting 1 hour after diazepam injection. Ten days after FSE, confocal images of VGAT/Gephyrin and parvalbumin (PV)-IR and stereological counts of PV neurons were obtained in sections through cortical layer V. Whole-cell voltage-clamp recordings from pyramidal neurons measured sIPSC and mIPSC frequency. Local field potential recordings were used to determine whether BD treatment, compared to vehicle, decreased the incidence of epileptiform activity in vitro. Statistical significance was tested with Wilcoxon test (p < 0.05).
Translational Research