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.
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TC-2153对富含纹状体的蛋白酪氨酸磷酸酶的药理抑制作用降低了海马兴奋性和癫痫发作倾向。
DOI：
10.1111/epi.17192
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发表时间：
2022-05
期刊：
影响因子：
5.6
通讯作者：
Chung, Hee Jung
中科院分区：
文献类型：
--
作者：
Walters, Jennifer M.;Kim, Eung Chang;Zhang, Jiaren;Jeong, Han Gil;Bajaj, Archit;Baculis, Brian C.;Tracy, Gregory C.;Ibrahim, Baher;Christian-Hinman, Catherine A.;Llano, Daniel A.;Huesmann, Graham R.;Chung, Hee Jung
STriatal 富含蛋白酪氨酸磷酸酶 (STEP) 是一种大脑特异性酪氨酸磷酸酶。膜结合的 STEP61 是在海马和皮质中表达的唯一亚型。 STEP 的基因缺失增强了海马体的兴奋性突触电流和长时程增强。然而，STEP61 是否影响癫痫易感性尚不清楚。在这里，我们研究了 STEP 抑制剂 TC-2153 对显示红藻氨酸 (KA) 诱导的癫痫持续状态的小鼠模型中癫痫发作倾向的影响及其对海马兴奋性的影响。成年雄性和雌性 C57BL/6J 小鼠腹腔注射载体（2.8% DMSO 生理盐水）或 TC-2153 (10 mg/kg)，3 小时后腹腔注射生理盐水或 KA (30 mg/kg)，然后监测行为癫痫发作。一部分雌性小鼠被切除卵巢（OVX）。 GCaMP6s 小鼠的急性海马切片用 DMSO 或 TC-2153 (10 μM) 处理 1 小时，然后在 ACSF 和氯化钾 (15 mM) 中孵育 2 分钟，然后进行活钙成像。在全细胞膜片钳记录之前，用 DMSO 或 TC-2153 (10 uM) 预处理分离的大鼠海马培养物 (DIV 8-10) 中的锥体神经元 1 小时。 TC-2153 治疗可显着降低 KA 诱发的癫痫发作严重程度，且女性中的趋势更大。 OVX 消除了 TC-2153 引起的女性癫痫发作严重程度的降低。 TC-2153 的应用显着降低了两性急性海马切片的整体兴奋性。令人惊讶的是，TC-2153 治疗使培养的海马锥体神经元的静息膜电位超极化，并降低放电率、电压骤降和超极化诱导电流 (Ih)。这项研究首次证明，TC-2153 对 STEP 的药理学抑制可降低男女癫痫发作的严重程度和海马活动，并抑制海马神经元兴奋性和 Ih。我们认为 TC-2153 的抗癫痫作用是通过其抑制神经元内在兴奋性的意外作用介导的。
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. Adult male and female C57BL/6J mice received intraperitoneal injection of either vehicle (2.8% DMSO in saline) or TC-2153 (10 mg/kg) and then either saline or KA (30 mg/kg) 3 hours later before being monitored for behavioral seizures. A subset of female mice was ovariectomized (OVX). Acute hippocampal slices from GCaMP6s mice were treated with either DMSO or TC-2153 (10 μM) for 1 hour, and then incubated in 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 uM) for 1 hour before whole-cell patch clamp recording. TC-2153 treatment significantly reduced KA-induced seizure severity, with greater trend seen in females. OVX abolished this TC-2153-induced decrease in seizure severity in females. 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. 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 anti-seizure effects of TC-2153 are mediated by its unexpected action on suppressing neuronal intrinsic excitability.
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影响因子：
3.7
作者：
Davis KE;Fox S;Gigg J
通讯作者：
Gigg J
影响因子：
3.7
作者：
Moosmang, S;Biel, M;Ludwig, A
通讯作者：
Ludwig, A
影响因子：
4.8
作者：
Huang, Jianying;Huang, Aijie;Yu, Han-Gang
通讯作者：
Yu, Han-Gang
DOI：
10.1523/jneurosci.0157-10.2010
发表时间：
2010-04-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kurup P;Zhang Y;Xu J;Venkitaramani DV;Haroutunian V;Greengard P;Nairn AC;Lombroso PJ
通讯作者：
Lombroso PJ
影响因子：
4.8
作者：
Nakazawa, T;Komai, S;Yamamoto, T
通讯作者：
Yamamoto, T