Role of nuclear calcium signaling in the control of activity-dependent modulation of BDNF gene expression in hippocampal neurons

神经营养因子脑源性神经营养因子（BDNF）在神经系统发育中具有多种作用，也是神经元可塑性和学习相关事件的关键参与者。BDNF可以诱导并帮助维持长期增强（LTP），这是一种突触效能的持续增加，被认为是学习和记忆的基础。BDNF有潜力用于改善与神经退行性疾病等相关的认知功能缺陷的治疗。外源性BDNF治疗的一个有吸引力的替代方案是调节内源性BDNF的表达。BDNF基因的表达不是恒定的，而是受到电活动和细胞内钙信号通路激活的调节。BDNF转录的一个重要调节因子是n -甲基- d -天冬氨酸（NMDA）受体；这种钙渗透性谷氨酸受体可以，取决于受体激活的位置（突触或突触外），增加或关闭BDNF转录。一些转录因子，尤其是CREB/CBP复合物，调节BDNF的转录。CREB/ cbp依赖性转录需要增加核钙浓度，这提高了核钙瞬态调节BDNF表达的可能性。本项目旨在探讨核钙在BDNF基因表达中的作用。我们计划开发技术来产生或干扰核钙信号。对BDNF基因转录调控机制的新认识可能会导致体内调节BDNF表达的新策略。

The neurotrophin brain-derived neurotrophic factor (BDNF) has many roles in the developing nervous system and is also a key player in neuronal plasticity and learning-related events. BDNF can induce and help to maintain long term potentiation (LTP), a persistent increase in synaptic efficacy that is thought to underlie learning and memory. BDNF harbors the potential to be used in therapies to improve deficits in cognitive functions associated with, for example, neurodegenerative diseases. An attractive alternative to the treatment with exogenous BDNF is the modulation of expression of the endogenous BDNF. BDNF gene expression is not constant but subject to regulation by electrical activity and the activation of intracellular calcium signaling pathways. An important regulator of BDNF transcription is the N-Methyl-D-Aspartate (NMDA) receptor; this calciumpermeable glutamate receptor can, depending on the localization of the receptor activated (synaptic or extrasynaptic), increase or shut-down BDNF transcription. Several transcription factors, most notably the CREB/CBP complex, regulate BDNF transcription. CREB/CBP-dependent transcription requires increases in the nuclear calcium concentration, raising the possibility that nuclear calcium transients regulate BDNF expression. Aim of this project is to investigate the role of nuclear calcium in BDNF gene expression. We plan to develop technologies to generate or interfere with nuclear calcium signaling. New mechanistic insight into the control of BDNF gene transcription may lead to novel strategies to modulate BDNF expression in vivo.