Pharmacological inhibition of STriatal‐Enriched protein tyrosine Phosphatase by TC‐2153 reduces hippocampal excitability and seizure propensity

Autor: Jennifer M. Walters, Eung Chang Kim, Jiaren Zhang, Han Gil Jeong, Archit Bajaj, Brian C. Baculis, Gregory C. Tracy, Baher Ibrahim, Catherine A. Christian‐Hinman, Daniel A. Llano, Graham R. Huesmann, Hee Jung Chung
Rok vydání: 2022
Předmět:
Zdroj: Epilepsia. 63:1211-1224
ISSN: 1528-1167
0013-9580
DOI: 10.1111/epi.17192
Popis: STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine phosphatase. Membrane-bound STEPAdult male and female C57BL/6J mice received intraperitoneal injection of either vehicle (2.8% dimethylsulfoxide [DMSO] in saline) or TC-2153 (10 mg/kg) and then either saline or KA (30 mg/kg) 3 h later before being monitored for behavioral seizures. A subset of female mice was ovariectomized (OVX). Acute hippocampal slices from Thy1-GCaMP6s mice were treated with either DMSO or TC-2153 (10 μM) for 1 h, and then incubated in artificial cerebrospinal fluid (ACSF) and potassium chloride (15 mM) for 2 min prior to live calcium imaging. Pyramidal neurons in dissociated rat hippocampal culture (DIV 8-10) were pre-treated with DMSO or TC-2153 (10 µM) for 1 h before whole-cell patch-clamp recording.TC-2153 treatment significantly reduced KA-induced seizure severity, with greater trend seen in female mice. OVX abolished this TC-2153-induced decrease in seizure severity in female mice. TC-2153 application significantly decreased overall excitability of acute hippocampal slices from both sexes. Surprisingly, TC-2153 treatment hyperpolarized resting membrane potential and decreased firing rate, sag voltage, and hyperpolarization-induced current (IThis study is the first to demonstrate that pharmacological inhibition of STEP with TC-2153 decreases seizure severity and hippocampal activity in both sexes, and dampens hippocampal neuronal excitability and I
Databáze: OpenAIRE
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