Mechanisms in the mouse hippocampus

Mechanisms of presynaptic modulation of synaptic strength in the mouse hippocampus

PhD student: Bernat Gonzalez i Llinares; Spain
Home Institute: Bordeaux Neurosciences Institute; Principle Investigator: Christophe Mulle
Host Institute: Neuroscience Campus Amsterdam; Principle Investigator; Matthijs Verhage

Executive Summary
Presynaptic modulation is a crucial factor in the adaptive capacity of the nervous system. The coupling between incoming action potentials and neurotransmitter secretion is modulated by (A) recent activity of the presynaptic axon that leads to the accumulation of residual calcium in the terminal, and (B) activation of presynaptic receptors by external signals. Despite the detailed description of these phenomena, the underlying mechanisms are still poorly understood. Moreover, recent evidence suggests that current theory of synaptic plasticity may need to be revised. Especially the accumulating evidence for presynaptic NMDA receptors and new retrograde signaling cascades shed a new light on the contribution of the nerve terminal to synaptic plasticity.

In this project we aim to exploit these new insights to revisit the signal transduction cascades that modulate synaptic strength and also to exploit new emerging technology to address these cascades on a single synapse level in the mouse hippocampus. The nerve terminal contains many Ca2+-binding proteins that may contribute to the translation of residual Ca2+-increases to secretion modulation. Furthermore, we also found that >100 presynaptic proteins are phosphorylated and may contribute to the translation of presynaptic receptor activation to secretion modulation. However, which of these many candidates are the dominant regulators and how their activities integrate is largely unknown.

Using patch clamp of presynaptic terminals, which is recently established in Bordeaux and the use of approximately 20 mutant mouse lines where presynaptic genes have been deleted, we aim to map these dominant regulators. Subsequently, we will map which presynaptic receptors alter the presynaptic cascades using classical pharmacology, but also photomanipulation, especially uncaging of caged glutamate.