Pharmacological inhibition of STriatal-Enriched protein tyrosine Phosphatase by TC-2153 reduces hippocampal excitability and seizure propensity.
Epilepsia
; 63(5): 1211-1224, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-35188269
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dimetil Sulfóxido
/
Hipocampo
Limite:
Animals
Idioma:
En
Revista:
Epilepsia
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA