Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9RT, UK.
AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, UK.
Transl Psychiatry. 2020 Jan 21;10(1):16. doi: 10.1038/s41398-020-0682-4.
Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17β-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia 1 (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.
谷氨酸能突触的丢失被认为是与精神神经疾病相关的关键细胞病理学，包括精神分裂症（SCZ）和重度抑郁症（MDD）。使用体内和体外系统对 SCZ 和 MDD 的遗传和细胞研究支持兴奋性突触功能障碍在这些疾病的病理生理学中的关键作用。最近的临床研究表明，雌激素 17β-雌二醇可以改善许多患者的症状。然而，迄今为止，我们对 17β-雌二醇发挥这些有益作用的机制的理解是有限的。在这项研究中，我们检验了这样一个假设，即 17β-雌二醇可以恢复与 SCZ 和 MDD 相关的突触丢失的细胞模型中的树突棘数量。野生型、突变型或 shRNA 介导的 DISC1（分裂失调蛋白 1）敲低的异位表达降低了原代皮质神经元中的树突棘密度。用 17β-雌二醇急性或慢性处理可使改变 DISC1 水平的神经元中的树突棘密度恢复到对照水平。此外，17β-雌二醇还降低了异位野生型和突变型 DISC1 聚集的程度。此外，17β-雌二醇还导致突触蛋白在突触处的富集，并增加了含有 PSD-95 或与突触前标记物 bassoon 重叠的树突棘的数量。总之，我们的数据表明，雌激素可以通过改变 DISC1 的表达来恢复丢失的兴奋性突触，这可能是通过 DISC1 及其相互作用的伴侣的运输来实现的。这些数据突出了雌激素通过调节树突棘数量来发挥其在 SCZ 和 MDD 中的有益作用的可能性。
