Authors :
Presenting Author: Fan Fei, PhD – Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University
Xia Wang, PhD – Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University
Xukun Fan, MS – Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University
Cenglin Xu, PhD – Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University
Zhong Chen, PhD – Zhejiang Chinese Medical University
Rationale:
Epilepsy is considered a circuit-level dysfunction associated with imbalanced excitation-inhibition, it is therapeutically necessary to identify key brain regions and related circuits in epilepsy. The subiculum is an essential participant in epileptic seizures, but the circuit mechanism underlying its role remains largely elusive. Here we deconstruct the diversity of subicular circuits in mouse models of epilepsy.
Methods:
In mice kindling and KA-induced seizure models, calcium fiber photometry was used to record real-time activity response of subicular pyramidal neurons and interneurons, retrograde monosynaptic viral tracing was used to map the circuit organization and reorganization patterns after chronic seizures, and optogenetics/chemogenetics were used to selectively manipulate pyramidal neuron and interneurons during epileptic seizures.
Results:
First, we found distinct functional dynamics of subicular parvalbumin+ and somatostatin+ interneurons during secondary generalized seizure. These interneuron subtypes have their biased circuit organizations in terms of both input and output patterns, which undergo distinct reorganization in chronic epileptic condition. Notably, somatostatin+ interneurons exert more effective feedforward inhibition onto pyramidal neurons compared to parvalbumin+ interneurons, which engenders consistent anti-seizure effects in TLE. As their downstream targets, excitatory subicular pyramidal neurons are also intrinsically activated during hippocampal seizures. Moreover, we found that the subiculum heterogeneously controls the generalization of hippocampal seizures by projecting to different downstream regions. Notably, anterior thalamus projecting subicular neurons bidirectionally mediate seizures, while entorhinal cortex-projecting subicular neurons act oppositely in seizure modulation. These two subpopulations are structurally and functionally dissociable. An intrinsically enhanced hyperpolarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission, thus contributing to the generalization of hippocampal seizures.
Conclusions:
These results demonstrate that subicular neurons and circuits have diverse roles in epilepsy, suggesting the necessity to precisely target specific subicular circuits for effective treatment of epilepsy.
Funding:
This project was supported by grants from the National Natural Science
Foundation of China (Grant No. 82022071, 81630098, 81821091, 81971208, 82304460) and Natural Science Foundation of Zhejiang Province (Grant No. LD22H310003)