Targeting ROCK2 to Restore Epileptic Synaptic Networks via Mitophagy Activation: Insights from Translational Imaging of SV2A In Vivo

Abstract Temporal lobe epilepsy (TLE) is increasingly recognized as a network‐level disorder, with contemporary strategies shifting focus from localized epileptic lesions to targeting dysfunctional epileptogenic networks. Leveraging recent advancements in neuroimaging genetics and the growing understanding of brain network remodeling in epilepsy, partial least squares regression is employed to integrate the altered synaptic connectome in TLE patients with a human transcriptomics dataset. The findings reveal a strong association between disruptions in synaptic density similarity networks and the spatial transcriptional profiles of TLE risk genes, identifying Rho‐associated protein kinase 2 ( ROCK2 ) as a pivotal gene. In TLE mouse models, treatment with a ROCK2 ‐specific inhibitor mitigates synaptic and neuronal loss, enhances network efficiency within the synaptic density connectome, and significantly reduces seizure frequency. Additionally, transcriptome profiling identifies multiple autophagy‐related pathways, and electron microscopy verifies that the administration of the ROCK2 inhibitor restores mitochondrial autophagy and reduces the accumulation of damaged mitochondria. These findings suggest that ROCK2 inhibitors may modulate synaptic networks and mitochondrial dysfunction, offering promising therapeutic potential for the treatment of TLE. This study provides novel insights into the genetic and molecular mechanisms driving epileptic network dysfunction and highlights ROCK2 as a compelling target for translational epilepsy research.