Targeting the Neuro-vascular Presynaptic Signalling in STROKE: Evidence and Therapeutic Implications.

Background: Stroke is one of the leading causes of death and long-term adult disability worldwide. Stroke causes neurodegeneration and impairs synaptic function. Understanding the role of synaptic proteins and associated signalling pathways in stroke pathology could offer insights into therapeutic approaches as well as improving rehabilitation-related treatment regimes.

Purpose: The current study aims to analyse synaptic transcriptome changes in acute and long-term post-stroke (1 day, 7 day timepoints), especially focusing on pre- and postsynaptic genes.

Methods: We performed data mining of the recent mRNA sequence from isolated mouse brain micro-vessels (MBMVs) after transient middle cerebral artery occlusion (tMCAO) stroke model. Using the SynGO (Synaptic Gene Ontologies and annotations) bioinformatics platform we assessed synaptic protein expression and associated pathways, and compared synaptic protein changes at 1 day and 7 day post-stroke.

Results: Enrichment analysis of the MBMVs identified significant alterations in the expression of genes related to synaptic physiology, synaptic transmission, neuronal structure, and organisation. We identified that the synaptic changes observed at the 7 day timepoint were initiated by the regulation of specific presynaptic candidates 1 day (24h) post-stroke, highlighting the significance of presynaptic regulation in mediating organising of synaptic structures and physiology. Analysis of transcriptomic data from human postmortem stroke brains confirmed similar presynaptic signalling patterns.

Conclusion: Our findings identify the changes in presynaptic gene regulation in micro-vessels following ischaemic stroke. Targeting presynaptic active zone protein signalling could represent a promising therapeutic target in mitigating ischaemic stroke.