An integrated transcriptomic and proteomic map of the mouse hippocampus at synaptic resolution

Area of Science:

• Neuroscience
• Molecular Biology
• Systems Biology

Background:

• Understanding brain molecular diversity necessitates spatially resolved transcript and protein maps.
• Existing methods lack comprehensive spatial resolution across brain regions and cellular compartments.

Purpose of the Study:

• To create a detailed molecular atlas of the mouse hippocampus with high spatial resolution.
• To investigate spatial transcript-protein relationships and their impact on neuronal organization and synaptic specificity.

Main Methods:

• Deep spatial molecular profiling using microdissection of hippocampal subregions and strata.
• Fluorescence-activated synaptosome sorting combined with transcriptomics and proteomics.
• Integration of translatome data to analyze protein synthesis and localization.

Main Results:

• Identification of thousands of locally enriched molecules (receptors, channels, metabolic, adhesion families).
• Revealed proteins linked or decoupled from mRNA levels, influenced by protein half-life.
• Demonstrated compartmental organization of pyramidal neurons, with distal dendrites relying on local protein synthesis.
• Classified CA1 synapses, highlighting roles of kinases, cytoskeletal elements, and adhesion molecules.

Conclusions:

• The study provides a comprehensive molecular atlas of the hippocampus and its synapses.
• Offers novel insights into the spatial regulation of gene expression and protein function in the brain.
• Establishes a framework for understanding molecular diversity and synaptic specificity.