Revealing the molecular, structural and functional heterogeneity of cortical synapses

Determine the molecular specializations underlying the functional diversity of synapses, such as the probability and short-term plasticity of neurotransmitter release. In vitro electrophysiology, two-photon imaging, LM and EM immunolocalization are combined to address these issues.

Understanding chemical synaptic neurotransmission in the CNS has been in the spotlight of neuroscience for many decades. A tremendous amount of information has been gathered regarding the molecular events leading to the release of neurotransmitter from synaptic vesicles, the diffusion of neurotransmitter molecules to their postsynaptic receptors and the activation of these receptors. At the same time, ultrastructural analysis of synapses revealed an enormous diversity in the shape and size of pre- and postsynaptic structures among central synapses. Recently, molecular approaches also revealed a large number of molecules involved in pre- and postsynaptic function, and the molecular diversity on many key players. However, it is still unknown how functional heterogeneity of synapses is generated and how alterations in synaptic geometry and molecular content affect synaptic function. The Laboratory of Cellular Neurophysiology combines in vitro electrophysiology and two-photon Ca2+ imaging with LM and EM molecular analysis of hippocampal GABAergic and glutamatergic synapses to address how diversity in the release probability and short-term plasticity of release arises from structural or molecular specializations. Furthermore, the laboratory also employs quantitative EM freeze-fracture replica immunogold localizations to reveal the molecular composition of structurally and functionally distinct presynaptic active zones and postsynaptic densities. The results shed new light on the structure-function relationship of central synapses and provide a molecular explanation of the diversity in synaptic function. The Laboratory also tests the hypothesis that the functional heterogeneity among synapses that belong to the same population (e.g. hippocampal CA1 pyramidal cells - CA1 O-LM cells) is the consequence of quantitative differences in the amounts of the same molecules and variations in their subsynaptic nano-distributions.

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