Modulation​ ​of​ ​neural​ ​information processing​ ​by​ ​P53

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Neuronal communication requires generation of action potentials as post-synaptic potentials are integratedin the soma. This, so-called, intracellular information transfer determines how information propagates along synaptically coupled neurons, and is gated by the action potential (AP) threshold. Modulation of AP threshold constitutes a potent way to control neuronal excitability and network communication. In this thesis, I address the role of P53, a protein central to regulation of cell replication and apoptosis, in controlling neuronal excitability. Although P53 is predominantly studied in cancer biology and during organ development, recent experimental evidence from the Department of Neurophysiology suggests that P53 might modulate neuronal excitability in post-mitotic neurons. Here using whole-cell voltage and current clamp recordings in acute brain slices, I experimentally show that targeted pharmacological modulation of P53 copy numbers in the cell causes increased neuronal excitability. Nutlin3a decreases the AP threshold, increases firing rate and spontaneous quantal neurotransmitter release in a cell-type specific manner. These results bring a unique insight into the contribution of proteins in cell-cycle and cell-death in normal neuronal function while introducing P53 as a potentially key transcriptional regulator​ ​controlling​ ​neuronal​ ​homeostasis​ ​in​ ​post-mitotic,​ ​differentiated​ ​neurons.
Faculteit der Sociale Wetenschappen