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

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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.