17β-雌二醇状态改变雌性大鼠的NMDAR功能和类抗精神病活性。
17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats.
作者信息
Holter Kimberly M, Klausner McKenna G, Hite Mary Hunter, Moriarty Carson T, Barth Samuel H, Pierce Bethany E, Iannucci Alexandria N, Sheffler Douglas J, Cosford Nicholas D P, Bimonte-Nelson Heather A, Raab-Graham Kimberly F, Gould Robert W
机构信息
Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Cancer Molecular Therapeutics Program. NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
出版信息
Mol Psychiatry. 2025 Apr 4. doi: 10.1038/s41380-025-02996-0.
Low 17β-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.
育龄女性体内17β-雌二醇（E2）水平较低，且绝经后E2会显著下降，这导致精神分裂症的症状严重程度增加（即认知功能障碍），并降低对抗精神病药物的反应。然而，其潜在机制尚不清楚。N-甲基-D-天冬氨酸受体（NMDAR）功能减退是精神分裂症病理生理学的一个因素，但E2耗竭对NMDAR功能的影响尚未得到充分描述。定量脑电图（qEEG），特别是γ波功率，是一种公认的皮质活动功能读数，在精神分裂症患者中升高，并且对NMDAR功能的改变敏感。本研究通过给有或没有E2植入物的去卵巢大鼠（分别为Ovx+E和Ovx）施用MK-801（NMDAR拮抗剂），利用qEEG和触摸屏认知评估来研究E2对NMDAR功能的影响。与Ovx+E大鼠相比，Ovx大鼠对MK-801诱导的γ波功率升高和注意力损害更敏感。进一步研究表明，这些影响是由突触GluN2A表达降低介导的。与临床报告一致，奥氮平（第二代抗精神病药物）在减轻Ovx大鼠中MK-801诱导的γ波功率升高方面效果较差。最后，我们研究了II组代谢型谷氨酸受体（mGlu）正变构调节剂（PAM）SBI-0646535作为E2缺乏条件下的一种新型治疗方法的抗精神病样活性。无论E2状态如何，SBI-0646535均可逆转MK-801诱导的γ波功率升高。总的来说，这些研究建立了E2缺乏与NMDAR功能之间的关系，这种关系部分依赖于GluN2A，支持E2缺乏会增加对NMDAR功能减退易感性的观点。这突出了在考虑抗精神病反应和设计新型药物疗法时检查年龄/激素特异性因素的必要性。
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