Excessive Excitatory Synapses Drive Pathological Neurons to Hyperexcitability in a Mouse Model of Focal Cortical Dysplasia
Abstract number :
3.021
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2024
Submission ID :
338
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Shuyang Wang, PhD – Zhongshan Hospital, Fudan University
Quansheng He, PhD – Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
Xin Wang, MD – Zhongshan Hospital, Fudan University
Yousheng Shu, PhD – Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University
Jing Ding, MD – Zhongshan Hospital, Fudan University
Rationale: Hyperactivation of the mTOR pathway caused by somatic mutation is closely related to type 2 focal cortical dysplasia (FCD), one of the most common causes of drug-resistance epilepsy. However, it remains controversial and poorly understood whether mutant neurons play a role in cortical hyperexcitability.
Methods: Using in utero electroporation, we generated type 2 FCD mouse model by overexpressing the upstream gene of mTOR pathway, PIK3CA. To probe the chief culprit of epilepsy, we examined the intrinsic excitability and excitation/inhibition(E/I) balance of mutant and nearby non-mutated neurons by whole-cell patch clamp recording. To decipher the net effects of intrinsic excitability and synaptic transmission, we delivered extracellular electric stimulation with varying current amplitudes to evoke action potentials (APs), and obtained the current threshold. Immunofluorescent staining and confocal imaging were used to analyze the spine density of secondary basal dendrites.
Results: (1) Compared with control neurons, mutant neurons showed a dramatic reduction in AP frequencies in response to intracellular current injections, whereas nearby non-mutated neurons showed no significant difference in AP frequencies. (2) The balance between excitatory and inhibitory synaptic inputs onto mutant neurons was shifted to favor excitation over inhibition. (3) Interestingly, the current threshold for evoked APs was significantly lower in mutant neurons, rather than nearby non-mutant neurons. (4) Meanwhile, dendritic spine density increased dramatically in mutant neurons.
Conclusions: Our results strongly suggest that excessive excitatory synaptic inputs may counteract with the low excitability in mutant neurons, leading to hyperexcitability in FCD.
Funding: This abstrat was supported by STI2030-Major Projects (2021ZD0202500, Y.S.), National Natural Science Foundation of China (32130044 and T2241002, Y.S.; 32100930, Q.H.), Program of Shanghai Academic/Technology Research Leader (21XD1400100, Y.S.), and China Postdoctoral Science Foundation (2020M681160, Q.H.).
Basic Mechanisms