In the brain, neurons are connected by billions of synapses. The postsynaptic density (PSD) is a densely packed structure located beneath the postsynaptic membrane of excitatory synapses. PSD proteins play essential roles in synaptic structure and function, and their dysfunction is linked to more than 100 brain disorders, including schizophrenia, depression, autism, and intellectual disabilities. Key to PSD protein function is their assembly into complexes and supercomplexes, which are known to vary in composition and spatial distribution within synapses, contributing to synapse diversity.
The Grant lab developed a pipeline for mapping synaptic complexes using high-speed confocal microscopy and advanced image analysis, revealing brain-wide synapse molecular diversity that changes throughout the lifespan in mice. At higher resolution, super-resolution microscopy showed that PSD95 proteins form nanoscale structures within synapses, adding nanoarchitecture as a further, as yet little understood, level to synapse diversity. These nanoscale arrangements are crucial for synaptic transmission and plasticity. Disease-associated mutations disrupt PSD supercomplex structures and synaptome architecture, particularly in models of autism and schizophrenia, but their impact on nanoarchitecture is unknown. The SYNarch project aimed to employ key PSD proteins to map diversity in synapse nanoarchitecture across regions of the mouse brain, providing a baseline for investigations into how mutations affect this fundamental level of synaptic protein organization, with implications for major brain disorders.
During SYNarch, a method was developed to evaluate synaptic nanoarchitecture using Förster resonance energy transfer (FRET) between PSD95 molecules, which was combined with the synaptome mapping pipeline. This new combination of resolution and scale uncovered the diversity of synapse nanoarchitecture across brain regions and lifespan in mice, and probed the impact of a schizophrenia mutation.
