The Solomon H Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2011 Apr 6;31(14):5414-25. doi: 10.1523/JNEUROSCI.2456-10.2011.
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 nuclear factor-κB (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 presynaptic and postsynaptic 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.
树突棘和突触的结构可塑性是调节神经元回路的基本机制，并可能为大脑中的信息存储提供持久的基础。我们发现，核因子-κB（NF-κB）转录因子的 p65 亚基是学习和记忆所必需的，它控制着小鼠海马神经元中兴奋性突触和树突棘的形成和形态。在快速棘突和突触发育期间，兴奋性传递会增加内源性 NF-κB 的活性。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 的缺失会降低棘突密度和棘突头部体积。NF-κB 在突触后神经元中的细胞自主功能足以调节前突触和后突触元件的形成。在体内突触发育过程中，NF-κB 的缺失同样会降低棘突密度，并降低突触反应的幅度。相比之下，在发育性突触发生达到平台期后，内源性 NF-κB 活性较低，p65 缺失不再减弱基础棘突密度。相反，成熟神经元中的 NF-κB 会被诱导新突触的需求激活，包括雌激素和短期的荷包牡丹碱，并且对于响应这些刺激上调棘突密度是必需的。p65 富含于树突棘中，使得局部蛋白-蛋白相互作用成为可能；然而，NF-κB 对棘突密度的影响需要转录，以及 NF-κB 对 PSD-95 的依赖性调节，PSD-95 是一个关键的突触后成分。总之，我们的数据定义了 NF-κB 在赋予诱导兴奋性突触和棘突密度变化所必需的转录调节方面的独特作用，但不是维持这些变化的作用。
