Ottawa Hospital Research Institute, Ottawa, ON K1H8M5, Canada.
Georgetown University School of Medicine, MedStar Georgetown Transplant Institute, Washington D.C. 2007, USA.
Neurobiol Dis. 2021 Jul;155:105397. doi: 10.1016/j.nbd.2021.105397. Epub 2021 May 17.
Subanesthetic doses of ketamine induce schizophrenia-like behaviors in mice including hyperlocomotion and deficits in working memory and sensorimotor gating. Here, we examined the effect of in vivo ketamine administration on neuronal properties and endocannabinoid (eCB)-dependent modulation of synaptic transmission onto layer 2/3 pyramidal neurons in brain slices of the prefrontal cortex, a region tied to the schizophrenia-like behavioral phenotypes of ketamine. Since deficits in working memory and sensorimotor gating are tied to activation of the tyrosine phosphatase PTP1B in glutamatergic neurons, we asked whether PTP1B contributes to these effects of ketamine. Ketamine increased membrane resistance and excitability of pyramidal neurons. Systemic pharmacological inhibition of PTP1B by Trodusquemine restored these neuronal properties and prevented each of the three main ketamine-induced behavior deficits. Ketamine also reduced mobilization of eCB by pyramidal neurons, while unexpectedly reducing their inhibitory inputs, and these effects of ketamine were blocked or occluded by PTP1B ablation in glutamatergic neurons. While ablation of PTP1B in glutamatergic neurons prevented ketamine-induced deficits in memory and sensorimotor gating, it failed to prevent hyperlocomotion (a psychosis-like phenotype). Taken together, these results suggest that PTP1B in glutamatergic neurons mediates ketamine-induced deficits in eCB mobilization, memory and sensorimotor gating whereas PTP1B in other cell types contributes to hyperlocomotion. Our study suggests that the PTP1B inhibitor Trodusquemine may represent a new class of fast-acting antipsychotic drugs to treat schizophrenia-like symptoms.
亚麻醉剂量的氯胺酮会在老鼠中引起类似精神分裂症的行为，包括过度活跃以及工作记忆和感觉运动门控缺陷。在这里，我们研究了体内给予氯胺酮对大脑前额叶皮层脑片中层 2/3 锥体神经元的神经元特性和内源性大麻素（eCB）依赖性突触传递调制的影响，该区域与氯胺酮类似精神分裂症的行为表型有关。由于工作记忆和感觉运动门控缺陷与谷氨酸能神经元中酪氨酸磷酸酶 PTP1B 的激活有关，我们想知道 PTP1B 是否有助于氯胺酮产生这些影响。氯胺酮增加了锥体神经元的膜电阻和兴奋性。全身性药理学抑制 PTP1B 通过 Trodusquemine 恢复了这些神经元特性，并防止了氯胺酮引起的三种主要行为缺陷中的每一种。氯胺酮还减少了锥体神经元中 eCB 的动员，同时出人意料地减少了它们的抑制性输入，而这些氯胺酮的作用被谷氨酸能神经元中 PTP1B 的消融所阻断或封闭。虽然谷氨酸能神经元中 PTP1B 的消融防止了氯胺酮引起的记忆和感觉运动门控缺陷，但它未能防止过度活跃（一种类似精神病的表型）。总的来说，这些结果表明，谷氨酸能神经元中的 PTP1B 介导了氯胺酮引起的 eCB 动员、记忆和感觉运动门控缺陷，而其他细胞类型中的 PTP1B 则有助于过度活跃。我们的研究表明，PTP1B 抑制剂 Trodusquemine 可能代表一类新的快速作用抗精神病药物，用于治疗类似精神分裂症的症状。
