The nanomodule as the dynamic, functional building block of the glutamate synapse

Synapses are responsible for transmitting, processing and storing information in the brain.

Recent ultrastructural data from rodent glutamate synapses has shown aligned clustering of key pre- and postsynaptic molecules in the sub 100 nm range.

A single synapse may contain more than one such nanocolumn, or nanomodule, prompting a reconsideration of the use of the classical quantal model for synaptic transmission.

The overarching hypothesis that will be tested functionally is that glutamate synaptic transmission and plasticity are based on dynamic nanomodules that presynaptically contain independent release locations for low- and high frequency transmission and postsynaptically with, or without, clusters of AMPA- and NMDA receptors.

We will test this hypothesis using electrophysiology and dynamic super resolution microscopy in rodent brain slices and in human inducible pluripotent stem cell derived 3-D neural aggregates.

The proposed research challenges the present understanding of key issues in synaptic physiology by adopting the novel concept of dynamic nanomodules.

An important part of the proposed project is also to contribute to develop more relevant human brain model systems for examining synaptic dysfunctions associated with human brain disorders, and for replacing animal based experimental models.