Deletion of FGF9 in GABAergic neurons causes epilepsy.

Abstract

Fibroblast growth factor 9 (FGF9) has long been assumed to modulate multiple biological processes, yet very little is known about the impact of FGF9 on neurodevelopment. Herein, we found that loss of Fgf9 in olig1 progenitor cells induced epilepsy in mice, with pathological changes in the cortex. Then depleting Fgf9 in different neural populations revealed that epilepsy was associated with GABAergic neurons. Fgf9 CKO in GABAergic neuron (CKOVGAT) mice exhibited not only the most severe seizures, but also the most severe growth retardation and highest mortality. Fgf9 deletion in CKOVGAT mice caused neuronal apoptosis and decreased GABA expression, leading to a GABA/Glu imbalance and epilepsy. The adenylate cyclase/cyclic AMP and ERK signaling pathways were activated in this process. Recombinant FGF9 proteoliposomes could significantly decrease the number of seizures. Furthermore, the decrease of FGF9 was commonly observed in serum of epileptic patients, especially those with focal seizures. Thus, FGF9 plays essential roles in GABAergic neuron survival and epilepsy pathology, which could serve as a new target for the treatment of epilepsy.

• Authors: Moran Guo, Can Cui, Xueqin Song, Lijing Jia, Duan Li, Xiuli Wang, Hui Dong, Yanqin Ma, Yaling Liu, Zhiqiang Cui, Le Yi, Zhongyao Li, Yue Bi, Yuanyuan Li, Yakun Liu, Weisong Duan, Chunyan Li
• Journal: Cell death & disease (Cell Death Dis) Vol. 12 Issue 2 Pg. 196 (02 19 2021) ISSN: 2041-4889 [Electronic] England
• PMID: 33608505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• Anticonvulsants
• FGF9 protein, human
• Fgf9 protein, mouse
• Fibroblast Growth Factor 9
• Recombinant Proteins
• Cyclic AMP
• Extracellular Signal-Regulated MAP Kinases
• Adenylyl Cyclases

Topics

• Adenylyl Cyclases (metabolism)
• Adult
• Animals
• Anticonvulsants (pharmacology)
• Apoptosis
• Case-Control Studies
• Cerebral Cortex (drug effects, metabolism, pathology, physiopathology)
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Epilepsy (metabolism, pathology, physiopathology, prevention & control)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblast Growth Factor 9 (blood, deficiency, genetics, pharmacology)
• GABAergic Neurons (drug effects, metabolism, pathology)
• Genetic Predisposition to Disease
• Humans
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Neural Stem Cells (drug effects, metabolism, pathology)
• Recombinant Proteins (pharmacology)
• Signal Transduction
• Young Adult