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At the single-cell level, there was no stereotyped sequence of neurons that always initiated an SLE; rather, ictogenesis seemed to occur stochastically, with random sets of neurons driving seizure onset in each individual seizure. This variability in seizure onset included both excitatory and inhibitory neurons as well as spatial heterogeneity from seizure to seizure within the SOZ. Longitudinal tracking of individual neurons revealed that seizure onset is stochastic at the single neuron level, suggesting that seizure initiation activates neurons in non-stereotyped sequences seizure to seizure. [Extracted from the article]

Could enhancing astrocyte glutamate uptake, by increasing GLT-1 expression, lead to novel treatment options for patients with refractory epilepsies? B Increasing astrocyte glutamate uptake is protective in a model of epilepsy b Peterson, Allison R., et al. I Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy i . This is important because although the vast majority of GLT-1 is expressed by astrocytes, it is also expressed by neurons, where it can have unique functions.[9] Therefore, precise cell-type-specific expression ensures virally expressed GLT-1 acts to enhance astrocyte glutamate uptake and limit excitatory neuronal transmission. [Extracted from the article]

Ultrastructural and Functional Changes at the Tripartite Synapse During Epileptogenesis in a Model of Temporal Lobe Epilepsy Clarkson C, Roy MS, Meredith GH, John AW, Maria ER, Karen SW. Exp Neurol. 2020;326:113196. doi: 10.1016/j.expneurol.2020.113196 The persistent unresponsiveness of many of the acquired epilepsies to traditional antiseizure medications has motivated the search for prophylactic drug therapies that could reduce the incidence of epilepsy in this at risk population. These studies are based on the idea of a period of epileptogenesis that can follow a wide variety of brain injuries. Epileptogenesis is hypothesized to involve changes in the brain not initially associated with seizures but which result finally in seizure prone networks. Understanding these changes will provide crucial clues for the development of prophylactic drugs. Using the repeated low-dose kainate rat model of epilepsy, we have studied the period of epileptogenesis following status epilepticus, verifying the latent period with continuous EEG monitoring. Focusing on ultrastructural properties of the tripartite synapse in the CA1 region of hippocampus, we found increased astrocyte ensheathment around both the presynaptic and postsynaptic elements, reduced synaptic AMPA receptor subunit and perisynaptic astrocyte GLT-1 expression, and increased number of docked vesicles at the presynaptic terminal. These findings were associated with an increase in frequency of the mEPSCs observed in patch clamp recordings of CA1 pyramidal cells. The results suggest a complex set of changes, some of which have been associated with increasingly excitable networks such as increased vesicles and mEPSC frequency, and some associated with compensatory mechanisms, such as increased astrocyte ensheathment. The diversity of ultrastructural and electrophysiological changes observed during epileptogeneiss suggests that potential drug targets for this period should be broadened to include all components of the tripartite synapse. [ABSTRACT FROM AUTHOR]

Identification of Epilepsy-Associated Neuronal Subtypes and Gene Expression Underlying Epileptogenesis Pfisterer U, Petukhov V, Demharter S, Meichsner J, Thompson JJ, Batiuk MY, Asenjo-Martinez A, Vasistha NA, Thakur A, Mikkelsen J, Adorjan I, Pinborg LH, Pers TH, von Engelhardt J, Kharchenko PV, Khodosevich K. Nat Commun. 2020;11(1):5038. doi:10.1038/s41467-020-18752-7 [published correction appears in Nat Commun. 2020;11(1):5988] Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110 000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and nonepileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy. [ABSTRACT FROM AUTHOR]