Transcriptionally downregulated GABAergic genes associated with synaptic density network dysfunction in temporal lobe...

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Temporal lobe epilepsy (TLE) is a neurological disorder characterized by synaptic loss and a genetic basis.
• Understanding whole-brain synaptic changes and gene expression in TLE patients is crucial but remains unclear.

Purpose of the Study:

• Investigate in vivo whole-brain synaptic density changes at a network level in TLE patients.
• Correlate synaptic network topology with gene expression patterns of TLE risk genes.

Main Methods:

• Utilized positron emission tomography with the [18F]SynVesT-1 radioligand to assess synaptic vesicle glycoprotein 2A.
• Analyzed two independent transcriptome datasets to examine gene expression.
• Constructed and analyzed the synaptic density similarity network (SDSN) topology.

Main Results:

• Observed decreased SDSN strength, reduced clustering, and increased path length in TLE, indicating network reorganization.
• Synaptic changes were prominent in temporo-limbic and fronto-parietal networks.
• SDSN connectivity changes correlated spatially with TLE risk gene expression, with 183 downregulated genes enriched in synaptic transmission pathways, including RBFOX1.

Conclusions:

• First evidence linking spatial expression patterns of downregulated risk genes to in vivo synaptic density network dysfunction in TLE.
• Findings suggest imaging-transcriptomic approaches can guide development of novel molecular and genetic network-based therapies for TLE.