Signaling mechanisms of the pro Brain Derived Neurotrophic Factor (proBDNF) and the prodomain BDNF (pBDNF) in neurons

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Summary of Research: Neurons are excitable cells that can communicate with other cells via electrical impulses, known as action potential. Neuronal firing activity is necessary to encode messages related to memory and attention. I study a neuronal pattern of activity called "persistent firing" in the brain. This activity refers to the property of neurons to sustain their activity while no stimulus is present and it is an essential mechanism for short-term memory. This pattern of activity must be tightly regulated to avoid hyperexcitability and to ensure that we memorize newly learned information. We need to understand how neuronal firing activity is regulated to understand how our brain functions. My long-term career goal is to elucidate cellular and molecular mechanisms regulating neuronal activity related to short-term memory. A hypothesis I test is that a group of secreted factors, known as proneurotrophic factors regulate neuronal firing pattern. To test this, I will employ electrophysiology, calcium imaging and behavioural studies in mice. My research will lead to new knowledge about the role of proneurotrophic factors on neuronal activity related to short-term memory, and new discoveries about the mechanism of action of these factors on neurons. Because we know almost nothing about the regulation of persistent firing, I anticipate that my research will have a significant impact on other laboratories studying the mechanisms of memory. I will focus on two short-term objectives to fill several gaps of knowledge: Objective 1) To elucidate the cellular and molecular mechanisms of action of the proneurotrophins proBrain Derived Neurotrophic Factor (proBDNF) on cortical neurons, with a specific attention on neuronal synaptic activity. I will test four non-mutually exclusive hypotheses. H1) proBDNF inhibits the activation of muscarinic receptors. H2) proBDNF inhibits TRPC4 and TRPC5 channels in cortical neurons. H3) proBDNF inhibits voltage-gated calcium channel (VGCC) in cortical neurons. H4) proBDNF promotes the hyperpolarization of cortical neurons via the opening of potassium channels. Objective 2) To characterize in detail the effect of a peptide resulting from the cleavage of the proBDNF on neuronal activity related to short term memory and attention. In physiological conditions the proneurotrophin proBDNF is cleaved into two entities: a peptide pBDNF and the mature BDNF. 20% of the human population carries a mutated form of the pBDNF known as pBDNFMet66. The exact functions of the standard form and the mutated form of these peptides are largely unknown. Over the next five years, I propose a series of experiments to better characterize the effect of the pBDNFMet66 on synaptic activity and persistent firing in cortical neurons. New data and knowledge obtained from Objective 1 and 2 will have a significant impact on the neurotrophin field and will considerably increase our understanding of mechanisms underlying memory formation.