A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.
A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis.
复制标题
DOI：
10.1523/jneurosci.2456-10.2011
复制
发表时间：
2011-04-06
期刊：
影响因子：
--
通讯作者：
Meffert MK
中科院分区：
文献类型：
--
作者：
Boersma MC;Dresselhaus EC;De Biase LM;Mihalas AB;Bergles DE;Meffert MK
树突棘和突触的结构可塑性是支配神经元回路的基本机制，并且可能形成大脑中信息存储的持久基础。我们发现，NF-κB转录因子的p65亚单位，这是学习和记忆所必需的，控制兴奋性突触和树突棘的形成和形态在小鼠海马神经元。内源性NF-κB活性在棘和突触快速发育期间通过兴奋性传递升高。在体外突触发生过程中，NF-κB增强树突棘和兴奋性突触密度，内源性p65的缺失降低棘密度和棘头体积。突触后神经元内NF-κB的细胞自主功能足以调节突触前和突触后元件的形成。在体内突触发育过程中，NF-κB的缺失同样降低了棘密度，也降低了突触反应的幅度。相比之下，发育突触发生达到稳定状态后，内源性NF-κB活性较低，p65缺陷不再减弱基底棘密度。相反，成熟神经元中的NF-κB被诱导对新突触的需求的刺激物激活，包括雌激素和短期荷包牡丹碱，并且对于响应于这些刺激物上调棘密度是必不可少的。p65在树突棘中富集，使得局部蛋白质-蛋白质相互作用成为可能;然而，NF-κB对棘密度的影响需要转录和PSD-95的NF-κ B依赖性调节，PSD-95是一种关键的突触后成分。总的来说，我们的数据定义了NF-κB在赋予诱导兴奋性突触和棘密度变化而不是维持兴奋性突触和棘密度所需的转录调节方面的独特作用。
Structural plasticity of dendritic spines and synapses is a fundamental mechanism governing neuronal circuits and may form an enduring basis for information storage in the brain. We find that the p65 subunit of the NF-κB transcription factor, which is required for learning and memory, controls excitatory synapse and dendritic spine formation and morphology in murine hippocampal neurons. Endogenous NF-κB activity is elevated by excitatory transmission during periods of rapid spine and synapse development. During in-vitro synaptogenesis, NF-κB enhances dendritic spine and excitatory synapse density and loss of endogenous p65 decreases spine density and spine head volume. Cell-autonomous function of NF-κB within the postsynaptic neuron is sufficient to regulate the formation of both pre- and post-synaptic elements. During synapse development in-vivo, loss of NF-κB similarly reduces spine density and also diminishes the amplitude of synaptic responses. In contrast, after developmental synaptogenesis has plateaued, endogenous NF-κB activity is low and p65-deficiency no longer attenuates basal spine density. Instead, NF-κB in mature neurons is activated by stimuli that induce demand for new synapses, including estrogen and short-term bicuculline, and is essential for upregulating spine density in response to these stimuli. p65 is enriched in dendritic spines making local protein-protein interactions possible; however, the effects of NF-κB on spine density require transcription and the NF-κB-dependent regulation of PSD-95, a critical postsynaptic component. Collectively, our data define a distinct role for NF-κB in imparting transcriptional regulation required for the induction of changes to, but not maintenance of, excitatory synapse and spine density.