Impact of changes in nuclear calcium signaling triggered by atlastin mutations and ER structural alterations on gene regulation and neuronal functions.

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Most plasticity-related processes in the nervous system, including learning and memory rely on calcium signaling. Calcium transients induced by synaptic activity stimulate local signaling events in the vicinity of the site of calcium entry into the cytosol. However, calcium rises can also spread throughout the neuron and convey signals to the cell nucleus leading to activation or repression of gene transcription. The neuronal endoplasmic reticulum (ER) plays an important role in cellular calcium handling. However, it is unknown if and how the morphological features of the ER impact on the spatial aspects and dynamics of calcium transients and calcium-dependent functions, in particular those in the cell nucleus. Many different proteins have been described in recent years that serve to shape the ER architecture. The tubule curving reticulons and the tubule fussing GTPase atlastins (ATLs) represent two groups of key players in the development and maintenance of ER morphology and have been implicated in human neurodegenerative diseases. The goal of this project is to investigate the impact of structural alteration of ER architecture on synaptic activity induced nuclear calcium signaling, gene expression, and neuronal functions. We will use loss-of–function mutations of the ER-shaping family of ATLs as well as RNA interferences in hippocampal neurons to alter ER morphology and study the consequences of it for the activation of nuclear calcium-driven genes that are known to be important for the consolidation of neuroadaptations and neuronal survival. In vitro studies will be focused on acquired neuroprotection, a synaptic activity- and nuclear calcium-dependent form of enhanced survival activity. In vivo studies will use stereotactic delivery to the mouse hippocampus of recombinant adeno associated viruses containing expression cassettes for GTPase-inactive, dominant negative ATLs or shRNAs targeting specific atlastins to determine the contribution of ER morphology to learning associated gene expression and hippocampus-dependent memory consolidation.