Hippocampal sclerosis (HS) is a common pathology encountered in mesial temporal lobe epilepsy (MTLE) as well as other epilepsy syndromes and in both surgical and post-mortem practice. The 2013 International League Against Epilepsy (ILAE) classification segregates HS into typical (type 1) and atypical (type 2 and 3) groups, based on the histological patterns of subfield neuronal loss and gliosis. In addition, granule cell reorganization and alterations of interneuronal populations, neuropeptide fibre networks and mossy fibre sprouting are distinctive features of HS associated with epilepsies; they can be useful diagnostic aids to discriminate from other causes of HS, as well as highlighting potential mechanisms of hippocampal epileptogenesis. The cause of HS remains elusive and may be multifactorial; the contribution of febrile seizures, genetic susceptibility, inflammatory and neurodevelopmental factors are discussed. Post-mortem based research in HS, as an addition to studies on surgical samples, has the added advantage of enabling the study of the wider network changes associated with HS, the long-term effects of epilepsy on the pathology and associated comorbidities. It is likely that HS is heterogeneous in aspects of its cause, epileptogenetic mechanisms, network alterations and response to medical and surgical treatments. Future neuropathological studies will contribute to better recognition and understanding of these clinical and patho-aetiological subtypes of HS.

/pdf/review-hippocampal-sclerosis-in-epilepsy-a-neuropathology-3rv7uzr07z.pdf

Review: Hippocampal sclerosis in epilepsy: a neuropathology review

Plasticity of intrinsic neuronal excitability.

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease.

/pdf/human-neocortical-expansion-involves-glutamatergic-neuron-1oraqfbugv.pdf

Human neocortical expansion involves glutamatergic neuron diversification

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

The absorption of glucose is electrogenic in the small intestinal epithelium. The major route for the transport of dietary glucose from intestinal lumen into enterocytes is the Na+/glucose cotransporter (SGLT1), although glucose transporter type 2 (GLUT2) may also play a role. The membrane potential of small intestinal epithelial cells (IEC) is important to regulate the activity of SGLT1. The maintenance of membrane potential mainly depends on the activities of cation channels and transporters. While the importance of SGLT1 in glucose absorption has been systemically studied in detail, little is currently known about the regulation of SGLT1 activity by cation channels and transporters. A growing line of evidence suggests that cytosolic calcium ([Ca2+]cyt) can regulate the absorption of glucose by adjusting GLUT2 and SGLT1. Moreover, the absorption of glucose and homeostasis of Ca2+ in IEC are regulated by cation channels and transporters, such as Ca2+ channels, K+ channels, Na+/Ca2+ exchangers, and Na+/H+ exchangers. In this review, we consider the involvement of these cation channels and transporters in the regulation of glucose uptake in the small intestine. Modulation of them may be a potential strategy for the management of obesity and diabetes.

Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters

Granule cells in the dentate gyrus are only sparsely active in vivo and survive hippocampal sclerosis (HS) during temporal lobe epilepsy better than neighboring cells. This phenomenon could be related to intrinsic properties specifically adapted to counteract excitation. We studied the mechanisms underlying the excitability of human granule cells using acute hippocampal slices obtained during epilepsy surgery. Patch-clamp recordings were combined with pharmacology, immunocytochemistry, and computer simulations. The input resistance of granule cells correlated negatively with the duration of epilepsy and the degree of HS. Hyperpolarization-activated, ZD7288-sensitive cation (I(H), HCN) currents and highly Ba(2+)-sensitive, inwardly rectifying K(+) (Kir) currents (and HCN1 and Kir2.2 protein) were present somatodendritically and further enhanced in patients with severe HS versus mild HS. The properties and function of I(H) were characterized in granule cells. Although I(H) depolarized the membrane, it strongly reduced the input resistance and shifted the current-frequency function to higher input values. The shunting influence of HCN and Kir was similar and these conductances correlated. Resonance was not observed. Simulations suggest that the combined upregulation of Kir and HCN conductances attenuates excitatory synaptic input, while stabilizing the membrane potential and responsiveness. Thus, granule cells homeostatically downscale their input-output transfer function during epilepsy.

Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

Action potential (AP) responses of dentate gyrus granule (DG) cells have to be tightly regulated to maintain hippocampal function. However, which ion channels control the response delay of DG cells is not known. In some neuron types, spike latency is influenced by a dendrotoxin (DTX)-sensitive delay current (I D ) mediated by unidentified combinations of voltage-gated K + (Kv) channels of the Kv1 family Kv1.1-6. In DG cells, the I D has not been characterized and its molecular basis is unknown. The response phenotype of mature DG cells is usually considered homogenous but intrinsic adaptations likely occur in particular in conditions of hyperexcitability, for example during temporal lobe epilepsy (TLE). In this study, we examined response delays of DG cells and underlying ion channel molecules by employing a new combination of gramicidin-perforated patch-clamp recordings in acute brain slices and single-cell reverse transcriptase quantitative polymerase chain reaction (SC RT-qPCR) experiments. An in vivo mouse model of TLE consisting of intrahippocampal kainate (KA) injection was used to examine epilepsy-related plasticity. Response delays of DG cells were DTX-sensitive and strongly increased in KA-injected hippocampi; Kv1.1 mRNA was elevated 10-fold, and the response delays correlated with Kv1.1 mRNA abundance on the single cell level. Other Kv1 subunits did not show overt changes in mRNA levels. Kv1.1 immunolabeling was enhanced in KA DG cells. The biophysical properties of I D and the delay heterogeneity between inner and outer DG cell layer were characterized. Using organotypic hippocampal slice cultures (OHCs), where KA incubation also induced I D upregulation, reversibility and neuroprotective potential for DG cells were tested. In summary, the AP timing of DG cells is effectively controlled via scaling of Kv1.1 subunit transcription. With this antiepileptic mechanism, DG cells delay their responses durin

/pdf/regulation-of-action-potential-delays-via-voltage-gated-2l5glasr2n.pdf

Regulation of action potential delays via voltage-gated potassium Kv1.1 channels in dentate granule cells during hippocampal epilepsy.

With Time After Kainate Treatment Excitatory Synaptic Input to Granule Cells Increases

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Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

Regulation of action potential delays via voltage-gated potassium Kv1.1 channels in dentate granule cells during hippocampal epilepsy.

With Time After Kainate Treatment Excitatory Synaptic Input to Granule Cells Increases