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• We describe the structure and connectivity of the subiculum. • We summarize the dysfunctional subiculum in epileptic brain. • Translational approaches targeting the subiculum are promising to treat epilepsy. • We pose open questions for future research and clinical translation challenges. The subiculum serves as the strategic core output of the hippocampus, through which neural activity exits the hippocampal proper and targets the entorhinal cortex and other more distant subcortical and cortical areas. The past decade has witnessed a growing interest in the subiculum, owing to discoveries revealing its critical role in regulating many physiological and pathophysiological processes. Notably, accumulating evidence from both clinical and experimental studies suggests that the subiculum plays a vital role in seizure initiation and propagation, in epilepsy. In this review, we briefly describe the structure and connectivity of the subiculum and then summarize the molecular and cellular mechanisms in the subiculum underlying the epileptic brain, in both epilepsy patients and animal models. Next, we review some translational approaches targeting the malfunctioned subiculum to treat epilepsy. Finally, we pose open questions for future research in the subiculum and their clinical translation challenges. [ABSTRACT FROM AUTHOR]

Aims: Pharmaco‐genetics emerges as a new promising approach for epileptic seizures. Whether it can modulate epileptogenesis is still unknown. Methods: Here, parvalbumin neurons and pyramidal neurons of the seizure focus were transfected with engineered excitatory Gq‐coupled human muscarinic receptor hM3Dq and engineered inhibitory Gi‐coupled human muscarinic receptor hM4Di, respectively. And their therapeutic value in mouse hippocampal kindling‐induced epileptogenesis was tested. Results: Pharmaco‐genetic activating parvalbumin neurons limitedly retarded the progression of behavioral seizure stage and afterdischarge duration (ADD) during epileptogenesis induced by kindling. Activating parvalbumin neurons delayed seizure development only in the early stage, but accelerated it in late stages. On the contrary, pharmaco‐genetic inhibiting pyramidal neurons robustly retarded the progression of seizure stages and ADDs, which greatly delayed seizure development in both early and late stages. Although both pharmaco‐genetic therapeutics efficiently alleviated the severity of acute kindling‐induced seizures, pharmaco‐genetic inhibiting pyramidal neurons were able to reverse the enhanced synaptic plasticity during epileptogenesis, compared with that of pharmaco‐genetic activating parvalbumin neurons. Conclusion: Our results demonstrated that pharmaco‐genetic inhibiting pyramidal neurons retard hippocampal kindling‐induced epileptogenesis and reverse the enhanced synaptic plasticity during epileptogenesis, compared with that of pharmaco‐genetic activating parvalbumin neurons. It suggests that pharmaco‐genetics targeting pyramidal neurons may be a promising treatment for epileptogenesis. [ABSTRACT FROM AUTHOR]

A universal drug delivery system (DDS) with brain-targeted ability is demanded to enhance antiepileptic therapeutic efficacy and reduce side effects in multiple types of epileptic seizures. In this study, we reported a micelle-based DDS possessing the brain-targeted ability and electro-responsive feature for universal delivery of antiepileptic drugs (AEDs). The system is fabricated by ferrocene (Fc)-conjugated D-a-tocopherol polyethylene glycol succinate and amphiphilic block copolymer, which improve the drug encapsulation of different AEDs. Interestingly, the intrinsic nature of TPGS-Fc including transferrin receptor-mediated transcytosis and efflux pump inhibition endows the system with high permeability across the blood-brain barrier. Based on the hydrophobic-hydrophilic transition of Fc, the micelles can respond to epileptiform discharges and thus release the loaded AEDs. Improved antiepileptic efficacy of the micelles has been demonstrated in acute, continuous, and chronic epilepsy models. In summary, we have developed a universal micelle-based DDS for various AEDs delivery, which provides a promising approach to on-demand therapy of different epileptic seizures. Electro-responsive micelles with controlled release of various anti-epileptic drugs and brain-targeted ability are designed for improving drug concentration in epileptic foci and enhancing therapeutic efficacy. [Display omitted] • Electro-responsive micelle has ability of universal anti-epileptic drugs delivery. • Transferrin-mediated transcytosis and P-gp inhibition enhance the efficacy bypass BBB. • TFP exerts electro-responsive release and improve drug concentration in epileptic foci. • TFP enhances therapeutic efficacy of anti-epileptic drugs. [ABSTRACT FROM AUTHOR]

Objective: The precise intervention of K‐Cl cotransporter isoform 2 (KCC2) as a promising target for drug‐resistant epilepsy remains elusive. Methods: Here, we used a CRISPRa system delivered by adeno‐associated viruses to specifically upregulate KCC2 in the subiculum to confirm its therapeutic potential in various in vivo epilepsy models. Calcium fiber photometry was used to reveal the role of KCC2 in the restoration of impaired GABAergic inhibition. Results: CRISPRa system effectively upregulated KCC2 expression both in in vitro cell culture and in vivo brain region. Delivery of CRISPRa with adeno‐associated viruses resulted in upregulating the subicular KCC2 level, contributing to alleviating the severity of hippocampal seizure and facilitating the anti‐seizure effect of diazepam in a hippocampal kindling model. In a kainic acid‐induced epilepticus status model, KCC2 upregulation greatly increased the termination percentage of diazepam‐resistant epilepticus status with the broadened therapeutic window. More importantly, KCC2 upregulation attenuated valproate‐resistant spontaneous seizure in a kainic acid‐induced chronic epilepsy model. Finally, calcium fiber photometry showed CRISPRa‐mediated KCC2 upregulation partially restored the impaired GABAA‐mediated inhibition in epilepsy. Interpretation: These results showed the translational potential of adeno‐associated viruses‐mediated delivery of CRISPRa for treating neurological disorders by modulating abnormal gene expression that is directly associated with neuronal excitability, validating KCC2 as a promising therapeutic target for treating drug‐resistant epilepsy. ANN NEUROL 2023;94:91–105 [ABSTRACT FROM AUTHOR]

The raphe nuclei, the primary resource of forebrain 5-HT, play an important but heterogeneous role in regulating subcortical excitabilities. Fundamental circuit organizations of different median raphe (MR) subsystems are far from completely understood. In the present study, using cell-specific viral tracing, Ca2+ fiber photometry and epilepsy model, we map out the forebrain efferent and afferent of different MR Pet+ subpopulations and their divergent roles in epilepsy. We found that PetMR neurons send both collateral and parallel innervations to different downstream regions through different subpopulations. Notably, CA3-projecting PetMR subpopulations are largely distinct from habenula (Hb)-projecting PetMR subpopulations in anatomical distribution and topological organization, while majority of the CA3-projecting PetMR subpopulations are overlapped with the medial septum (MS)-projecting PetMR subpopulations. Further, using Ca2+ fiber photometry, we monitor activities of PetMR neurons in hippocampal-kindling seizure, a classical epilepsy model with pathological mechanisms caused by excitation-inhibition imbalance. We found that soma activities of PetMR neurons are heterogeneous during different periods of generalized seizures. These divergent activities are contributed by different projection-defined PetMR subpopulations, manifesting as increased activities in CA3 but decreased activity in Hb resulting from their upstream differences. Together, our findings provide a novel framework of MR subsystems showing that projection-defined MR Pet+ subpopulations are topologically heterogenous with divergent circuit connections and are diversely implicated in seizures. This may help in the understanding of heterogeneous nature of MR 5-HTergic subsystems and the paradox roles of 5-HTergic systems in epilepsy. • PetMR neurons send both collateral and parallel innervations to different regions through different subpopulations. • PetMR-CA3 and PetMR-Hb neurons are largely distinct subpopulations that receive divergent upstream inputs. • PetMR neurons shows heterogenous activities in seizure contributed by different projection-defined subpopulations. • PetMR-CA3 and PetMR-Hb neurons respond oppositely during generalized seizures. [ABSTRACT FROM AUTHOR]

Previous studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated. In the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models. We found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [gamma-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the antiseizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the antiseizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons. These findings underscore the notable antiseizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy. [ABSTRACT FROM AUTHOR]