Inhibition of mTOR by rapamycin has been shown to suppress seizures in TSC/PTEN genetic models. Rapamycin, when applied immediately before or after a neurological insult, also prevents the development of spontaneous recurrent seizures (epileptogenesis) in an acquired model. In the present study, we examined the mTOR pathway in rats that had already developed chronic spontaneous seizures in a pilocarpine model. We found that mTOR is aberrantly activated in brain tissues from rats with chronic seizures. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduces seizure activity. Finally, mTOR inhibition also significantly suppresses mossy fiber sprouting. Our findings suggest the possibility for a much broader window for intervention for some acquired epilepsies by targeting the mTOR pathway.

SummaryMicroglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippo-campal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention.

Fatty acid-binding proteins (FABPs) act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. Recent studies have demonstrated the ability of FABPs to simultaneously regulate metabolic and inflammatory pathways. We investigated the role of adipocyte FABP and epithelial FABP in the development of experimental autoimmune encephalomyelitis to test the hypothesis that these FABPs impact adaptive immune responses and contribute to the pathogenesis of autoimmune disease. FABP-deficient mice exhibited a lower incidence of disease, reduced clinical symptoms of experimental autoimmune encephalomyelitis and dramatically lower levels of proinflammatory cytokine mRNA expression in CNS tissue as compared with wild-type mice. In vitro Ag recall responses of myelin oligodendrocyte glycoprotein 35–55-immunized FABP−/− mice showed reduced proliferation and impaired IFN-γ production. Dendritic cells deficient for FABPs were found to be poor producers of proinflammatory cytokines and Ag presentation by FABP−/− dendritic cells did not promote proinflammatory T cell responses. This study reveals that metabolic-inflammatory pathway cross-regulation by FABPs contributes to adaptive immune responses and subsequent autoimmune inflammation.

Summary: Purpose:To evaluate the effect of slow-frequency repetitive transcranial magnetic stimulation (SF-rTMS) on interictal epileptiform activity and seizure frequency in a patient with medically refractory partial seizures due to focal cortical dysplasia.Methods: A 9-cni circular coil was positioned over the area of cortical dysplasia. One hundred stimuli given at 0.5 Hz at 5% below motor threshold were given biweekly for four consecutive weeks. The EEG was recorded for 30 min before and after the first 100 stimuli. The number of seizures during the month of stimulation was compared with that of the month before stimulation.Results: Stimulation was associated with a 70% reduction in the frequency of seizures and a 77% reduction in the frequency of interictal spikes. No seizures occurred during stimulation.Conclusions: SF-rTMS was safe and well tolerated in this patient. The reduction in seizures and interictal spikes associated with SF-rTMS supports the concept of SF-rTMS-induced cortical inhibition. Key Words: Magnetic-StimulationEpilepsy-Treatment-Dy splasia.Partial seizures due to focal cortical dysplasia rarely respond to treatment with anticonvulsants (1 ). Although advances in the surgical treatment of such lesions have led to improved outcome, the probability of seizure freedom is substantially less than in other localizationrelated epilepsies (2). Other nonpharmacologic treatment options are needed for patients with epilepsy due to focal cortical dysplasia.Electrophysiologic methods of producing changes in cortical excitability became available with the advent of transcranial magnetic stimulation (TMS) ( 3 ) . TMS may be given as a single pulse or as a train of repetitive stimuli (r-TMS). r-TMS is further subdivided into fast frequency (FF r-TMS) for rates >1 Hertz and slow frequency (SF r-TMS) for rates <1 Hertz. Both frequencies induce immediate cortical suppression, but only FF r-TMS produces subsequent cortical excitation (4). Furthermore, FF r-TMS has side effects ranging from subject discomfort to seizure induction (5).In contrast, SF r-TMS is neither painful nor epileptoAccepted September 10, 1999. Address correspondence and reprint requests to Dr. M. Gruenthal at Department of Neurology, University of Louisville School of Medicine, 500 South Preston Street, HSC 113, Louisville, KY 40292, U.S.A. E-mail: MOgrueOl @athena.louisville.edu genic. A pilot trial of SF r-TMS-induced cortical inhibition was found to be effective in treating depression (6). A separate open, uncontrolled trial demonstrated similar result in depressed and schizophrenic patients (7). SF r-TMS reduces motor cortex excitability in humans (8) and reduces amygdala-kindled seizures in rats (9), suggesting a possible therapeutic role in localizationrelated epilepsy. We present a case in which SF r-TMS was used successfully in a patient with medically refractory partial seizures associated with focal cortical dysplasia.

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