Hemstedt Thekla J, Bengtson C Peter, Ramírez Omar, Oliveira Ana M M, Bading Hilmar
Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany.
Department of Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
J Neurosci. 2017 Jul 19;37(29):6946-6955. doi: 10.1523/JNEUROSCI.2345-16.2017. Epub 2017 Jun 16.
Nuclear calcium is an important signaling end point in synaptic excitation-transcription coupling that is critical for long-term neuroadaptations. Here, we show that nuclear calcium acting via a target gene, VEGFD, is required for hippocampus-dependent fear memory consolidation and extinction in mice. Nuclear calcium-VEGFD signaling upholds the structural integrity and complexity of the dendritic arbor of CA1 neurons that renders those cells permissive for the efficient generation of synaptic input-evoked nuclear calcium transients driving the expression of plasticity-related genes. Therefore, the gating of memory functions rests on the reciprocally reinforcing maintenance of an intact dendrite geometry and a functional synapse-to-nucleus communication axis. In psychiatric and neurodegenerative disorders, therapeutic application of VEGFD may help to stabilize dendritic structures and network connectivity, which may prevent cognitive decline and could boost the efficacy of extinction-based exposure therapies. This study uncovers a reciprocal relationship between dendrite geometry, the ability to generate nuclear calcium transients in response to synaptic inputs, and the subsequent induction of expression of plasticity-related and dendritic structure-preserving genes. Insufficient nuclear calcium signaling in CA1 hippocampal neurons and, consequently, reduced expression of the nuclear calcium target gene VEGFD, a dendrite maintenance factor, leads to reduced-complexity basal dendrites of CA1 neurons, which severely compromises the animals' consolidation of both memory and extinction memory. The structure-protective function of VEGFD may prove beneficial in psychiatric disorders as well as neurodegenerative and aging-related conditions that are associated with loss of neuronal structures, dysfunctional excitation-transcription coupling, and cognitive decline.
核钙是突触兴奋-转录偶联中一个重要的信号转导终点，对长期神经适应性变化至关重要。在此，我们表明，通过靶基因VEGFD发挥作用的核钙，是小鼠海马依赖性恐惧记忆巩固和消退所必需的。核钙-VEGFD信号通路维持了CA1神经元树突分支的结构完整性和复杂性，使这些细胞能够有效地产生突触输入诱发的核钙瞬变，从而驱动可塑性相关基因的表达。因此，记忆功能的调控依赖于完整的树突形态和功能性突触-细胞核通讯轴的相互强化维持。在精神疾病和神经退行性疾病中，VEGFD的治疗应用可能有助于稳定树突结构和网络连接性，这可能预防认知衰退，并提高基于消退的暴露疗法的疗效。本研究揭示了树突形态、响应突触输入产生核钙瞬变的能力以及随后诱导可塑性相关和树突结构维持基因表达之间的相互关系。CA1海马神经元中核钙信号不足，进而导致核钙靶基因VEGFD（一种树突维持因子）表达降低，导致CA1神经元基底树突复杂性降低，这严重损害了动物的记忆巩固和消退记忆。VEGFD的结构保护功能可能在精神疾病以及与神经元结构丧失、兴奋-转录偶联功能失调和认知衰退相关的神经退行性疾病和衰老相关病症中具有益处。
