Role of microtubule affinity‐regulating kinases in epilepsy: A novel therapeutic strategy

Background and Purpose Microtubule affinity‐regulating kinases (MARKs), implicated in synaptic remodelling processes, have attracted attention as key regulatory targets in numerous neurological and psychiatric disorders. However, their role in epilepsy remains unclear. This study examined the involvement of MARK1 or MARK2 in regulating epilepsy‐induced synaptic plasticity. Experimental Approach The roles of MARKs in normal or epilepsy rats were evaluated through hippocampus CA1 region‐specific gene knockdown or overexpression of MARK1 or MARK2, as well as systemic administration of the novel small‐molecule MARK inhibitor, PCC0105003. Cognitive functions and anxiety‐like behaviours were assessed in epileptic rats. Synaptic plasticity‐related signalling changes were detected via western blots, immunofluorescence, and quantitative real‐time polymerase chain reaction (qRT‐PCR). Key Results Epileptiform discharges were observed in EEGs of rats overexpressing MARK1 or MARK2 in the absence of chemoconvulsant‐induced epilepsy. MARK1 or MARK2 knockdown in hippocampus CA1 and systemic administration of PCC0105003 ameliorated seizure behaviours and the number of seizure‐like events (SLEs) in EEG recordings, and attenuated the cognitive deficit and anxiogenic‐like behaviours. In contrast, overexpression of MARK1 or MARK2 in the hippocampus CA1 led to exacerbated epileptic‐like behaviours and reduced therapeutic effects of PCC0105003. Blocking the signalling of MARKs likely led to a reversal of synaptic transmission, which was mediated by the suppression of NMDA2B/GluR1/CAMKII signalling pathway in epileptic rats. Conclusion and Implications MARK1/2‐mediated excitatory synaptic transmission plays a key role in the development of epilepsy. Pharmacological inhibitors of MARKs, such as PCC0105003, may represent a novel therapeutic strategy for the management of epilepsy.