Targeting the Mouse Ventral Hippocampus in the Intrahippocampal Kainic Acid Model of Temporal Lobe Epilepsy

Zeidler, Zachary; Brandt-Fontaine, Mikaela; Leintz, Caara; Krook-Magnuson, Chris; Netoff, Theoden I.; Krook-Magnuson, Esther

doi:10.1523/eneuro.0158-18.2018

Cited by 66 publications

(84 citation statements)

References 118 publications

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“…The location of the KA injection was chosen to allow for chronic 2-photon imaging of the dorsal dentate gyrus ipsilateral to the KA injection. Intra-ventral hippocampal KA injection results in epileptogenesis and seizure profiles similar to that found in the dorsal hippocampal KA model (Zeidler et al, 2018).…”

Section: Kainic Acid Injectionsupporting

confidence: 60%

“…KA was injected unilaterally into the ventral HPC ipsilateral to the viral injection site to induce status epilepticus, simulating the initial insult that leads to epileptogenesis in humans (Levesque andAvoli, 2013, Zeidler et al, 2018). The KA injection site was chosen to minimize associated gliosis and cell loss within the imaging field of view, thereby permitting imaging of the DG within the vicinity of the main insult to the network (Zeidler et al, 2018). Three days later, a chronic imaging window was implanted over the dorsal DG providing optical access necessary for celltype-specific imaging of the GC layer in the dorsal blade of the DG.…”

Section: Two-photon Calcium Imaging Of the Epileptic Dg In Vivomentioning

confidence: 99%

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Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

Sparks

Liao

et al. 2020

Preprint

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Highlights• We relate electrographic signatures of epilepsy to microcircuit dynamics at single-cell resolution • The chronically epileptic dentate gyrus granule cell network is organized in lineagespecific pathological ensembles• A novel generative model framework for ensemble recruitment relates local field potential signatures to microcircuit activation during interictal epileptiform discharges • Adult-born granule cell-dominated ensembles are disproportionately represented among the inferred ensembles • The most active ensemble during an interictal epileptiform discharge can be decoded directly from the local field potential spectrum • This Latent Ensemble Recruitment model of cell recruitment by interictal events is the first application of Bayesian topic modeling to in vivo two-photon calcium imaging data Abstract Temporal lobe epilepsy (TLE) is characterized by recurrent seizures driven by synchronous neuronal activity. The dentate gyrus (DG) region of the hippocampal formation is highly reorganized in chronic TLE; in particular, pathological remodeling of the "dentate gate" is thought to open up pathological conduction pathways for synchronous discharges and seizures in the mesial temporal lobe. However, this pathophysiological framework lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the DG at the microcircuit level. In particular, the relative contribution of developmentally defined subpopulations of adultborn (abGCs) and mature (mGCs) granule cells to epileptiform network events remains unknown. To address this question, we optically recorded activity dynamics of identified populations of abGCs and mGCs during interictal epileptiform discharges (IEDs) in mice with chronic TLE. We find that disjoint subsets of IEDs differentially recruit abGC and mGC populations. We used these observations to develop a neural topic modeling framework, under which we find that the epileptic DG network organizes into disjoint, cell-type specific pathological ensembles, a subset of which are recruited by each IED. We found that statistics of this ensemble structure are highly conserved across animals, with abGCs disproportionately driving network activity in the epileptic DG during IEDs. Our results provide the first in vivo characterization of activity dynamics of identified GC subpopulations in the epileptic DG, the first microcircuit-level correlates of IEDs in vivo, and reveal a specific contribution of abGCs to interictal epileptic events.

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Section: Kainic Acid Injectionsupporting

confidence: 60%

Section: Two-photon Calcium Imaging Of the Epileptic Dg In Vivomentioning

confidence: 99%

Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

Sparks

Liao

et al. 2020

Preprint

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“…Seizure events are processed automatically based on user‐identified characteristics of spikes including amplitude, peak width, spike frequency and deflection (positive, negative, or both), and the resulting post‐detection seizure duration of all events were confirmed via manual inspection (Zeidler et al . ). No consistent effects on time to next seizure were noted.…”

Section: Methodsmentioning

confidence: 97%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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Key pointsr On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy.r In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures.r On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures.r Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity.Abstract Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells -the fastigial nucleus -in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest Martha Streng received a BA in Neuroscience and Behaviour from Mount Holyoke College and a PhD in Neuroscience from the University of Minnesota, Twin Cities, where she studied the encoding of motor predictive and feedback information by Purkinje cells during online motor control tasks. Her current research focuses on the characterization of cerebellar circuitry and output channels in health and disease. that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

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“…Object Recognition Memory (ORM) and Objection Location Memory (OLM) testing was performed as previously described [ 49,57,61 ] with minor modifications. In addition to the ORM and OLM tests, subjects underwent an additional task which was similar to the ORM, but odorants are presented on cotton swabs as a way to test odor recognition memory (OdorRM, modified after ref.…”

Section: Behavioral Experimentsmentioning

confidence: 99%

A novel population of long-range inhibitory neurons

Wick

Tetzlaff

Krook-Magnuson

2019

Preprint

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The hippocampus, a brain region important for spatial navigation and episodic memory, benefits from a rich diversity of neuronal cell-types. Recent work suggests fundamental gaps in our knowledge of these basic building blocks (i.e., neuronal types) in the hippocampal circuit, despite extensive prior examination. Through the use of an intersectional genetic viral vector approach, we report a novel hippocampal neuronal population, which has not previously been characterized, and which we refer to as LINCs. LINCs are GABAergic, but, in addition to broadly targeting local CA1 cells, also have longrange axons. LINCs are thus both interneurons and projection neurons. We demonstrate that LINCs, despite being relatively few in number, can have a strong influence on both hippocampal and extrahippocampal network synchrony and function. Identification and characterization of this novel cell population advances our basic understanding of both hippocampal circuitry and neuronal diversity.

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Targeting the Mouse Ventral Hippocampus in the Intrahippocampal Kainic Acid Model of Temporal Lobe Epilepsy

Abstract: Visual Abstract

Cited by 66 publications

References 118 publications

Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

Adult-born granule cells support pathological microcircuits in the chronically epileptic dentate gyrus

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

A novel population of long-range inhibitory neurons

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