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

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

  • Epilepsia. 2022 May;63(5):1211-1224. doi: 10.1111/epi.17192.
Jennifer M Walters 1 2,  Eung Chang Kim 2,  Jiaren Zhang 2,  Han Gil Jeong 2,  Archit Bajaj 2,  Brian C Baculis 1 2,  Gregory C Tracy 2,  Baher Ibrahim 1 2 3,  Catherine A Christian-Hinman 1 2 3,  Daniel A Llano 1 2 3,  Graham R Huesmann 1 2 3 4 5,  Hee Jung Chung 1 2 3
Affiliations

Affiliations

  • 1 Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
  • 2 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
  • 3 Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
  • 4 Department of Neurology, Carle Foundation Hospital, Urbana, Illinois, USA.
  • 5 Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
PMID: 35188269 DOI: 10.1111/epi.17192
Abstract

Objective: STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific tyrosine Phosphatase. Membrane-bound STEP61 is the only isoform expressed in hippocampus and cortex. Genetic deletion of STEP enhances excitatory synaptic currents and long-term potentiation in the hippocampus. However, whether STEP61 affects seizure susceptibility is unclear. Here we investigated the effects of STEP inhibitor TC-2153 on seizure propensity in a murine model displaying kainic acid (KA)-induced status epilepticus and its effect on hippocampal excitability.

Methods: Adult 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.

Results: 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 (Ih ) of cultured hippocampal pyramidal neurons.

Significance: This 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 Ih . We propose that the antiseizure effects of TC-2153 are mediated by its unexpected action on suppressing neuronal intrinsic excitability.

Keywords

STEP; TC-2153; excitability; kainic acid; seizures.

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