Activation of prefrontal parvalbumin interneurons ameliorates treatment-resistant working memory deficit even under continuous antipsychotic treatment in a mouse model of schizophrenia
Activation of prefrontal parvalbumin interneurons ameliorates treatment-resistant working memory deficit even under continuous antipsychotic treatment in a mouse model of schizophrenia
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即使在精神分裂症小鼠模型的持续抗精神病治疗下，前额叶小白蛋白中间神经元的激活也能改善治疗抵抗性工作记忆缺陷
DOI：
10.1101/2023.02.27.530344
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ohkawa Noriaki
中科院分区：
文献类型：
--
作者：
Arime Yosefu;Saitoh Yoshito;Ishikawa Mikiko;Kamiyoshihara Chikako;Uchida Yasuo;Fujii Kazuki;Takao Keizo;Akiyama Kazufumi;Ohkawa Noriaki
精神分裂症的一个关键的未满足的医疗需求是对认知缺陷的补救。然而，它们的神经回路机制仍然没有得到解决。此外，尽管精神分裂症患者不能停止服用抗精神病药物，由于高利率的中断诱导复发，以前的研究使用动物模型的精神分裂症没有考虑这些临床situations. METHODS在这里，我们采用多维的方法，包括组织学分析在前边缘皮层，LC-MS/MS为基础的体内多巴胺D2受体占有率分析抗精神病药物，使用化学发生学操作对小鼠进行体内钙成像和行为分析，以研究慢性苯环利定（PCP）给药的小鼠模型中工作记忆缺陷的神经机制和潜在的治疗干预，所述慢性苯环利定给药类似于精神分裂症的行为学。慢性PCP给药导致兴奋性和抑制性突触异常，包括锥体神经元的树突棘、囊泡谷氨酸转运体1（VGLUT 1）阳性终末和小清蛋白（PV）阳性GABA能中间神经元。连续奥氮平在纹状体中实现了多巴胺D2受体占用率的持续治疗窗（60-80%），但对PCP处理小鼠的这些突触异常和工作记忆缺陷没有影响。我们发现，选择性的前边缘PV激活，使用hM 3D（Gq）-DREADD系统确认在体内钙成像，恢复工作记忆缺陷，即使在连续奥氮平treatment.CONCLUSIONSOUR研究提出了一种可能性，即在前额叶PV神经元的干预导致一个附加治疗的抗精神病药物靶向改善精神分裂症的耐药认知缺陷。
BACKGROUNDOne of the critical unmet medical needs in schizophrenia is a remedy for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. In addition, despite the patients with schizophrenia cannot stop taking antipsychotics due to a high rate of discontinuation-induced relapse, previous studies using animal models of schizophrenia have not considered these clinical situations.METHODSHere, we employ multi-dimensional approaches, including histological analysis in the prelimbic cortex, LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotic drugs, in vivo calcium imaging and behavioral analyses of mice using chemogenetic manipulation, to investigate neural mechanisms and potential therapeutic interventions for working memory deficit in a mouse model with chronic phencyclidine (PCP) administration that resembles the schizophrenia symptomatology.RESULTSChronic PCP administration led to abnormalities in excitatory and inhibitory synapses, including dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons, in layer 2–3 of the prelimbic cortex. Continuous olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not affect these synaptic abnormalities and working memory deficit in the PCP-treated mice. We found that the selective prelimbic PV activation, using hM3D(Gq)-DREADD system confirmed by in vivo calcium imaging, restored working memory deficit, even under continuous olanzapine treatment.CONCLUSIONSOur study raises a possibility that intervention in prefrontal PV neurons leads to an add-on therapy to antipsychotics targeting amelioration of treatment-resistant cognitive deficits in schizophrenia.
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DOI：
10.1101/2022.04.05.487077
发表时间：
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期刊：
bioRxiv
影响因子：
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作者：
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