Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well-tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology.

Neurogenesis in the dentate gyrus has been implicated in cognitive functions including learning and memory, and may be abnormal in major neuropsychiatric disorders such as depression. Dentate neurogenesis is regulated by interactions between extrinsic factors and intrinsic transcriptional cascades that are currently not well understood. Here we show that Tbr2 (also known as Eomes), a T-box transcription factor expressed by intermediate neuronal progenitors (INPs), is critically required for neurogenesis in the dentate gyrus of developing and adult mice. In the absence of Tbr2, INPs are depleted despite augmented neural stem cell (NSC) proliferation, and neurogenesis is halted as the result of failed neuronal differentiation. Interestingly, we find that Tbr2 likely promotes lineage progression from NSC to neuronal-specified INP in part by repression of Sox2, a key determinant of NSC identity. These findings suggest that Tbr2 expression in INPs is critical for neuronal differentiation in the dentate gyrus, and that INPs are an essential stage in the lineage from NSCs to new granule neurons in the dentate gyrus.

Objective We recently reported successful treatment of a child with febrile infection‐related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin‐1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. Methods Levels of IL1β and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell‐based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real‐time polymerase chain reaction. Results Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1β in a cell‐based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. Interpretation Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision‐making. Ann Neurol 2019;85:526–537

Neurogenesis - the production of new neurons - occurs in two specialized niches in the adult brain, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule neurons that integrate into the granule cell layer. In the SVZ, NSCs generate a more diverse cohort of new neurons, including GABAergic, dopaminergic, and glutamatergic neurons, all of which migrate to the olfactory bulb through the rostral migratory stream. In both adult neurogenic niches, specific transcription factors have been shown to direct fate specification and lineage commitment. This review summarizes current progress on the transcriptional control of glutamatergic neurogenesis in the SGZ and SVZ, highlighting commonalities as well as differences in their transcriptional programs. In particular, we focus on work from our laboratory and others indicating that precise, sequential expression of transcription factors regulates the progression from NSC to lineage-committed progenitor, and ultimately regulates the production and differentiation of adult-born glutamatergic neurons.

During acute neuroinflammation, increased levels of cytokines within the brain may contribute to synaptic reorganization that results in long-term changes in network hyperexcitability. Indeed, inflammatory cytokines are implicated in synaptic dysfunction in epilepsy and in an array of degenerative and autoimmune diseases of the central nervous system. Current tools for studying the impact of inflammatory factors on neural networks are either insufficiently fast and sensitive or require complicated and costly experimental rigs. Calcium imaging offers a reasonable surrogate for direct measurement of neuronal network activity, but traditional imaging paradigms are confounded by cellular heterogeneity and cannot readily distinguish between glial and neuronal calcium transients. While the establishment of pure neuron cultures is possible, the removal of glial cells ignores physiologically relevant cell-cell interactions that may be critical for circuit level disruptions induced by inflammatory factors. To overcome these issues, we provide techniques and algorithms for image processing and waveform feature extraction using automated analysis of spontaneous and evoked calcium transients in primary murine cortical neuron cultures transduced with an adeno-associated viral vector driving the GCaMP6f reporter behind a synapsin promoter. Using this system, we provide evidence of network perturbations induced by the inflammatory cytokines TNFα, IL1β, and IFNγ.

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CNS regeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long-term prognosis in patients. Approachable molecular targets that stimulate CNS repair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibody HIgM12. HIgM12 reverses motor deficits in chronically demyelinated mice, a model of MS. Here we identified polysialic acid (PSA) attached to the Neural Cell Adhesion Molecule (NCAM) as the antigen for HIgM12 by using different NCAM knockout strains and through PSA removal from the NCAM protein core. Antibody binding to CNS tissue and primary cells, antibody-mediated cell adhesion and neurite outgrowth on HIgM12-coated nitrocellulose was detected only in the presence of PSA as assessed by Western blotting, immunoprecipitation, immunocytochemistry and histochemistry. We conclude that HIgM12 mediates it's in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases.

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