Mechanisms of the Presynaptic Function
In our laboratory, we use electrophysiology and optical imaging analytical strategies in combination with modern molecular-biology techniques to study short-term synaptic plasticity (STP) at levels that range from knowledge of the molecules involved to computational implications or implications in CNS diseases.
Synapses have traditionally been thought to passively transmit coded signals in presynaptic action potential trains. More recent studies show that synapses play an active role in processing the transmitted information. This modulation is the result of rapid changes in the synaptic potential that takes place during episodes of repeated use (common during physiological patterns of synaptic discharge). These rapid, transitory changes are known as short-term plasticity. We currently lack a coherent framework to study the underlying mechanisms of cell biology, the role this phenomena plays in the normal functioning of the central nervous system, or its importance in disease.
Practically all synapses show substantial levels of STP during routine use, so understanding STP may reveal key aspects of brain function and its computational capacity. A better understanding of this phenomenon will be of enormous medical importance, as STP dysfunctions occur in the initial stages of neurological diseases such as epilepsy, Parkinson's and Alzheimer's disease.
Our work over the last 10 years has focused on characterizing the basic principles of STP between the Schaffer collaterals and the CA1 region of the hippocampus. We've reported two new processes (synaptic "augmentation" and depression), whose balance determines neurotransmitter release rates. We have used mathematical models to analyze this information and to establish a limited series of parameters that allow us to diagnose the state of excitatory synaptic transmission1.This has allowed us to identify synaptic fatigue and the molecules synapsin and SV2 as promising targets for developing neuroprotective strategies2.
Research projects currently in progress are comparing the fundamental properties of STP in synapses in the hippocampus compared to giant calyx of Held synapses in the auditory system. We have also launched an initiative to determine the relationship between nanostructures in the presynaptic terminals and endogenous neuroprotective mechanisms. In collaboration with the National Center for Microscopy and Imaging Research (NCMIR, San Diego, CA, USA), we are developing high-resolution tomography methods to determine the ultra-structure of presynaptic terminals. The goal is to apply this method to the structural analysis of genetically modified mice with abnormal presynaptic function and to establish the correlation between structure and function. We also bring our experience in electrophysiology to the projects of other researchers in fundamental neuroscience3.
- 1Gabriel et al, J Neuroscience 2011
- 2García-Pérez et al, Epilepsia 2015
- 3Marco et al, Nature Medicine, Wesseling et al, JAMA Neurology 2015