Hippocampal GABAergic Inhibitory Interneurons

Pelkey, Kenneth A.; Chittajallu, Ramesh; Craig, Michael T.; Tricoire, Ludovic; Wester, Jason C.; McBain, Chris J

doi:10.1152/physrev.00007.2017

Cited by 709 publications

(849 citation statements)

References 1,273 publications

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“…Human and mouse Na v 1.1 is predominantly expressed in parvalbumin-positive γ-aminobutyric acid (GABA) interneurons, 6 in brain structures playing a critical role in seizure generation and spread, 7,8 such as the hippocampus or cortex. 9,10 Na v 1.1 haploinsufficiency impairs Na + currents and action potential firing of GABAergic interneurons, leading to an elevated excitation/inhibition ratio in forebrain structures. 6 Moreover, functional and structural dentate gyrus deficits in the hippocampal network parallel spontaneous seizure onset.…”

Section: Introductionmentioning

confidence: 99%

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

et al. 2020

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Objective To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease‐modifying activity of the 5HT2 receptor agonist fenfluramine. Methods We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage‐gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single‐cell RNA‐Seq, morphometric analysis of transgenic reporter‐labeled γ‐aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. Results Homozygous mutant (scn1labmut/mut) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20‐minute recording; P < .0001; one‐way analysis of variance). Drop‐Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high‐frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. Significance Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first‐time evidence for potential disease modification by fenfluramine.

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Section: Introductionmentioning

confidence: 99%

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

et al. 2020

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“…Each of these characteristics depends on the combined properties of the pre-and post-synaptic neurons and varies widely across and within neural systems. The rodent hippocampus has long served as a discovery sandbox for synaptic biophysics (Buzsaki, 1984;Freund & Buzsaki, 1996;Nicoll, 2017;Pelkey et al, 2017). Both excitatory and inhibitory synapses in the hippocampal formation exhibit tremendous diversity in a number of mechanisms including synchronous or asynchronous release (Daw, Tricoire, Erdelyi, Szabo, & McBain, 2009;Szabo, Holderith, Gulyas, Freund, & Hajos, 2010;Szabo, Papp, Mate, Szabo, & Hajos, 2014), failure rate (Losonczy, Biro, & Nusser, 2004;Maccaferri, Roberts, Szucs, Cottingham, & Somogyi, 2000), and potentiation or depression (Alle, Jonas, & Geiger, 2001;Jappy, Valiullina, Draguhn, & Rozov, 2016).…”

Section: Introductionmentioning

confidence: 99%

A comprehensive knowledge base of synaptic electrophysiology in the rodent hippocampal formation

Moradi

Ascoli

2019

Hippocampus

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The cellular and synaptic architecture of the rodent hippocampus has been described in thousands of peer‐reviewed publications. However, no human‐ or machine‐readable public catalog of synaptic electrophysiology data exists for this or any other neural system. Harnessing state‐of‐the‐art information technology, we have developed a cloud‐based toolset for identifying empirical evidence from the scientific literature pertaining to synaptic electrophysiology, for extracting the experimental data of interest, and for linking each entry to relevant text or figure excerpts. Mining more than 1,200 published journal articles, we have identified eight different signal modalities quantified by 90 different methods to measure synaptic amplitude, kinetics, and plasticity in hippocampal neurons. We have designed a data structure that both reflects the differences and maintains the existing relations among experimental modalities. Moreover, we mapped every annotated experiment to identified potential connections, that is, specific pairs of presynaptic and postsynaptic neuron types. To this aim, we leveraged http://hippocampome.org, an open‐access knowledge base of morphologically, electrophysiologically, and molecularly characterized neuron types in the rodent hippocampal formation. Specifically, we have implemented a computational pipeline to systematically translate neuron type properties into formal queries in order to find all compatible potential connections. With this system, we have collected nearly 40,000 synaptic data entities covering 88% of the 3,120 potential connections in http://hippocampome.org. Correcting membrane potentials with respect to liquid junction potentials significantly reduced the difference between theoretical and experimental reversal potentials, thereby enabling the accurate conversion of all synaptic amplitudes to conductance. This data set allows for large‐scale hypothesis testing of the general rules governing synaptic signals. To illustrate these applications, we confirmed several expected correlations between synaptic measurements and their covariates while suggesting previously unreported ones. We release all data open‐source at http://hippocampome.org in order to further research across disciplines.

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“…Of the EB‐entrapped neurons, large, oval, or spindle neurons (>15 µm) localized in the hilus and molecular layer were immunopositive for PV, which is exclusively expressed in GABAergic interneurons such as basket cells and axo‐axonic chandelier cells in the hippocampal dentate gyrus (Kosaka et al, ). These interneurons form synapses within the dentate gyrus (Booker & Vida, ; Freund & Buzsáki, ; Pelkey et al, ). Large EB‐positive PV‐negative neurons localized along the inner margin of the GCL including the SGZ may be “sporadically lurking Huntingtin‐associated protein 1‐immunoreactive cells,” which are localized in the SGZ and identified as PV‐negative basket cells (Islam et al, ).…”

Section: Discussionmentioning

confidence: 99%

Constitutive accessibility of circulating proteins to hippocampal neurons in physiologically normal rats

et al. 2020

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Introduction Although the hippocampus (HIP) is thought impermeable to blood‐borne proteins because of the integrity of the blood–brain barrier (BBB), it was recently suggested to be susceptible to hydrophilic hormones. The present study determined the accessibility of blood‐borne signal molecules such as hormones to hippocampal neurons in physiologically normal rats. Methods As a probe for accessibility, Evans blue dye (EB) that rapidly binds to albumin (Alb), which is impermeable to the BBB, was injected intravenously. To increase the vascular permeability of the BBB, a daily single administration of angiotensin II (Ang II) was applied intravenously for seven consecutive days. Results Fifteen minutes after the injection of EB, histological observation revealed that a number of neurons had entrapped and accumulated EB into their cell bodies in the hippocampal dentate gyrus in all rats. Of these, relatively large oval neurons (>15 µm) in the hilus and molecular layer showed parvalbumin immunopositivity, indicating they are GABAergic interneurons. The population of EB‐accumulating neurons (approximately 10 µm) were localized in the inner margin of the granule cell layer, suggesting they were granule cells. However, the number of EB‐positive neurons did not change in rats treated with Ang II compared with vehicle injection. Conclusions These findings suggest an intriguing possibility that blood‐derived proteins such as hormones have access to hippocampal neurons constitutively in the absence of stimuli that increase the vascular permeability of the BBB in a physiologically normal state.

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Hippocampal GABAergic Inhibitory Interneurons

Cited by 709 publications

References 1,273 publications

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

A comprehensive knowledge base of synaptic electrophysiology in the rodent hippocampal formation

Constitutive accessibility of circulating proteins to hippocampal neurons in physiologically normal rats

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