Sellers Katherine J, Erli Filippo, Raval Pooja, Watson Iain A, Chen Ding, Srivastava Deepak P
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK.
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London London, UK ; Department of Biotechnology and Biosciences, Univeristy of Milano-Bicocca Milano, Italy.
Front Cell Neurosci. 2015 Apr 14;9:137. doi: 10.3389/fncel.2015.00137. eCollection 2015.
In the mammalian forebrain, the majority of excitatory synapses occur on dendritic spines. Changes in the number of these structures is important for brain development, plasticity and the refinement of neuronal circuits. The formation of excitatory synapses involves the coordinated formation of dendritic spines and targeting of multi-protein complexes to nascent connections. Recent studies have demonstrated that the estrogen 17β-estradiol (E2) can rapidly increase the number of dendritic spines, an effect consistent with the ability of E2 to rapidly influence cognitive function. However, the molecular composition of E2-induced spines and whether these protrusions form synaptic connections has not been fully elucidated. Moreover, which estrogen receptor(s) (ER) mediate these spine-morphogenic responses are not clear. Here, we report that acute E2 treatment results in the recruitment of postsynaptic density protein 95 (PSD-95) to novel dendritic spines. In addition neuroligin 1 (Nlg-1) and the NMDA receptor subunit GluN1 are recruited to nascent synapses in cortical neurons. The presence of these synaptic proteins at nascent synapses suggests that the machinery to allow pre- and post-synapses to form connections are present in E2-induced spines. We further demonstrate that E2 treatment results in the rapid and transient activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and the mammalian target of rapamycin (mTOR) signaling pathways. However, only ERK1/2 and Akt are required for E2-mediated spinogenesis. Using synthetic receptor modulators, we further demonstrate that activation of the estrogen receptor beta (ERβ) but not alpha (ERα) mimics rapid E2-induced spinogenesis and synaptogenesis. Taken together these findings suggest that in primary cortical neurons, E2 signaling via ERβ, but not through ERα, is capable of remodeling neuronal circuits by increasing the number of excitatory synapses.
在哺乳动物的前脑，大多数兴奋性突触位于树突棘上。这些结构数量的变化对大脑发育、可塑性以及神经回路的优化至关重要。兴奋性突触的形成涉及树突棘的协同形成以及多蛋白复合物向新生连接的靶向定位。最近的研究表明，雌激素17β-雌二醇（E2）可迅速增加树突棘的数量，这一效应与E2快速影响认知功能的能力相一致。然而，E2诱导的树突棘的分子组成以及这些突起是否形成突触连接尚未完全阐明。此外，尚不清楚哪些雌激素受体（ER）介导这些树突棘形态发生反应。在此，我们报告急性E2处理导致突触后致密蛋白95（PSD-95）募集到新的树突棘上。此外，神经连接蛋白1（Nlg-1）和NMDA受体亚基GluN1被募集到皮质神经元的新生突触中。这些突触蛋白在新生突触中的存在表明，在E2诱导的树突棘中存在使突触前和突触后形成连接的机制。我们进一步证明，E2处理导致细胞外信号调节激酶1/2（ERK1/2）、Akt和雷帕霉素哺乳动物靶标（mTOR）信号通路的快速和短暂激活。然而，E2介导的树突棘形成仅需要ERK1/2和Akt。使用合成受体调节剂，我们进一步证明雌激素受体β（ERβ）而非α（ERα）的激活模拟了E2快速诱导的树突棘形成和突触形成。综上所述，这些发现表明，在原代皮质神经元中，E2通过ERβ而非ERα发出信号，能够通过增加兴奋性突触的数量来重塑神经回路。
