The pathophysiological mechanism of epilepsy has not been fully elucidated. Abnormal synaptic plasticity in the hippocampus may be an important trigger. Decorin (DCN), an extracellular matrix protein, may affect synaptic remodeling by regulating the mTOR signalling pathway. However, its role and molecular mechanism in epilepsy remain unclear. In this study, a chronic epilepsy mouse model induced by kainic acid (KA) was established. The protein expression of DCN in the hippocampus was significantly increased during the occurrence of epilepsy. By using an adeno-associated virus (AAV) to knock down DCN expression in the hippocampus, the effect of DCN on the occurrence of epilepsy was explored. The experiments revealed that knocking down DCN could significantly shorten the duration of status epilepticus, reduce the frequency and severity of spontaneous seizures, etc. Moreover, DCN knockdown could improve synaptic remodelling by downregulating the expression of key proteins, such as AMPA/NMDA receptor subunits (GluN2A, GluN2B) and PSD95, on the postsynaptic membrane, and reducing the abnormal increase in dendritic spine density and the number of synaptic vesicles. Molecular mechanism studies revealed that DCN physically interacts with mTOR protein, and its knockdown coincided with reduced phosphorylation and activation of mTOR. These findings suggest a potential link between DCN and mTOR signalling. Therefore, the DCN-mTOR axis emerges as a potential target for modulating the excessive synaptic transmission associated with epilepsy. This study is the first to reveal that DCN participates in the pathological process of epilepsy by regulating mTOR-dependent synaptic plasticity, providing experimental evidence that the DCN-mTOR axis can be targeted to intervene in synaptic homeostasis imbalance.
Liu et al. (Tue,) studied this question.