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Objective: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI. Methods: An adeno‐associated virus (AAV)‐Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory‐associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV‐Cre or AAV‐vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video‐electroencephalographic monitoring. Results: AAV‐Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV‐Cre‐injected mice had reduced neuronal death in dentate gyrus detected by Fluoro‐Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV‐Cre‐injected mice exhibited a decrease in incidence of PTE. Significance: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE. [ABSTRACT FROM AUTHOR]

Objective: Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in the brain and other organs, and severe neurological symptoms, such as epilepsy. Abnormal vascular endothelial growth factor (VEGF) expression may promote angiogenesis in kidney and lung tumors in TSC and has been identified in brain specimens from TSC patients, but the role of VEGF and vascular abnormalities in neurological manifestations of TSC is poorly defined. In this study, we investigated abnormalities in brain VEGF expression, cerebral blood vessel anatomy, and blood–brain barrier (BBB) structure and function in a mouse model of TSC. Methods: Tsc1GFAPCKO mice were used to investigate VEGF expression and vascular abnormalities in the brain by Western blotting and immunohistochemical analysis of vascular and BBB markers. In vivo two‐photon imaging was used to assess BBB permeability to normally impenetrable fluorescently labeled compounds. The effect of mechanistic target of rapamycin (mTOR) pathway inhibitors, VEGF receptor antagonists (apatinib), or BBB stabilizers (RepSox) was assessed in some of these assays, as well as on seizures by video‐electroencephalography. Results: VEGF expression was elevated in cortex of Tsc1GFAPCKO mice, which was reversed by the mTOR inhibitor rapamycin. Tsc1GFAPCKO mice exhibited increased cerebral angiogenesis and vascular complexity in cortex and hippocampus, which were reversed by the VEGF receptor antagonist apatinib. BBB permeability was abnormally increased and BBB‐related tight junction proteins occludin and claudin‐5 were decreased in Tsc1GFAPCKO mice, also in an apatinib‐ and RepSox‐dependent manner. The BBB stabilizer (RepSox), but not the VEGF receptor antagonist (apatinib), decreased seizures and improved survival in Tsc1GFAPCKO mice. Significance: Increased brain VEGF expression is dependent on mTOR pathway activation and promotes cerebral vascular abnormalities and increased BBB permeability in a mouse model of TSC. BBB modulation may affect epileptogenesis and represent a rational treatment for epilepsy in TSC. [ABSTRACT FROM AUTHOR]

Objective: Neurostimulation is an emerging treatment for patients with drug‐resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. Methods: We performed high‐throughput testing of high‐frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. Results: We found that the spike‐suppressive effects of high‐frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. Significance: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti‐seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. Plain Language Summary: In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode's placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure‐like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy. [ABSTRACT FROM AUTHOR]

A highly efficient and simple route for the synthesis of 2-substituted benzo[d]thiazoles has been developed by nickel catalyzed cross-coupling of 2-methylthiobenzo[d]thiazoles with aryl and alkenylaluminum reagents. Various 2-(hetero)aryl and 2-alkenyl substituted benzo[d]thiazoles derivatives can be obtained with 31–94% isolated yields using 4 mol% NiCl2(dppf)/4 mol% 2,2′-bipyridine as the catalyst under mild reaction conditions. The coupling reaction can be carried out smoothly whether the electron donor group or electron withdrawing group is on the aromatic ring of organic aluminum reagents or 2-methylthiobenzo[d]thiazoles derivatives. Furthermore, the broad substrate scope and the typical maintenance of vigorous efficiency on a gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[d]thiazoles derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed. [ABSTRACT FROM AUTHOR]