Authors :
Suji Wang, PhD – Nanjing University
Zhang-Peng Chen, PhD – Nanjing University
Presenting Author: Chao Yan, PhD – Nanjing University
Rationale:
The importance of glia cells in epileptogenesis and epilepsy progression is increasingly recognized. However, the mechanisms underlying the contribution of neuron-glia crosstalk to the pathology of epilepsy are not completely understood. In this study, we aim to define the molecular and functional phenotypes of epilepsy-related glia cells including astrocytes and microglia.Methods:
We collected fresh surgical tissues from patients with temporal lobe epilepsy (TLE) and performed single-nucleus RNA sequencing as well as lipidomics studies. We used the kainic acid mouse model to confirm the findings in human patients. For cellular and molecular mechanism studies, we performed primary culture and co-culture of neurons and glia cells. We also generated several conditional knockout mice for investigating the function of certain lipid metabolism genes in astrocytes or microglia.
Results:
Previously, we showed that in patients with temporal lobe epilepsy (TLE) and mouse models of epilepsy, excessive lipid accumulation in astrocytes leads to the formation of lipid-accumulated reactive astrocytes (LARA), which promotes neuronal hyperactivity and disease progression through the upregulation of the adenosine receptor A2AR. In the current study, we identify a subpopulation of microglia in patients with TLE that exhibits dysfunction in lipid metabolism and elevated expression of SCD1, a critical enzyme in the lipid metabolism pathway. Both pharmacological blockade and genetic knockout of SCD1 alleviated epilepsy symptoms in mouse models. Mechanistic studies revealed that SCD1-positive microglia produce and release high levels of lysophosphatidylcholine (LPC), which promotes neuronal hyperactivity via the presynaptic LPA2R receptor on excitatory neurons. Conclusions:
Our results unveil a previously unknown role of lipid metabolism reprogramming in glia cells in the pathology of epilepsy and provide new therapeutic targets for drug-resistant epilepsy.
Funding:
Funded by National Natural Science Foundation of China grant 82373856.