Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory

Bui, Anh; Nguyen, Tai D.; Limouse, Charles; Kim, Hannah K.; Szabó, Gergely; Felong, Sylwia; Maroso, Mattia; Soltész, Iván

doi:10.1126/science.aan4074

Cited by 223 publications

(291 citation statements)

References 32 publications

(52 reference statements)

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“…The three IHKA groups displayed deficits in the OLM task compared to nonepileptic controls at 10 days post‐IHKA (control: DI = 29.5 ± 2.2, n = 6; IHKA: DI = 5.9 ± 4.6, n = 10, P < .001), 3‐4 months post‐IHKA (control: DI = 35.6 ± 4.0, n = 5; IHKA: DI = 11.0 ± 2.8, n = 9, P = .002), and 6‐7 months post‐IHKA (control: DI = 30.6 ± 3.7, n = 14; IHKA: DI = 7.9 ± 2.0, n = 9, P < .001) (Figure B, Table ). As we showed in a previous study, IHKA mice displayed deficits compared with nonepileptic controls and did not discriminate effectively between the moved and unmoved object (DI < 20). Quantification of the total exploration time of the objects remained the same between IHKA‐treated and control animals at 10 days (control: 4.0 ± 0.4 s; IHKA: 4.5 ± 0.3 s), 3‐4 months after IHKA (control: 3.9 ± 0.4 s; IHKA: 4.1 ± 0.2 s), and 6‐7 months after IHKA (control: 5.0 ± 0.2 s; IHKA: 4.5 ± 0.4 s), indicating that the deficit in OLM performance in IHKA animals was not due to lack of exploration (Figure C).…”

Section: Resultssupporting

confidence: 69%

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

et al. 2020

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Objective To determine if closed‐loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well‐established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory. Methods Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin‐expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed‐loop light intervention of seizures. Animals that responded to closed‐loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed‐loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory. Results Animals that received closed‐loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult. Significance Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

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Section: Resultssupporting

confidence: 69%

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

et al. 2020

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“…To examine if the effects of inhibitory and excitatory DREADDs are specific to ventral but not dorsal MCs, we injected AAVs expressing mCherry, Hm4Di-mCherry or Hm3Dq-mCherry bilaterally into the dorsal hilus of Drd2-cre mice expressing Cre in dorsal MCs (Puighermanal et al, 2015). We confirmed that all mCherry-expressing cells are positive for GluR2/3, a marker for dorsal MCs (Fujise et al, 1997) ( (Bui et al, 2018;Hsu et al, 2016), these results indicate that the activation of longrange projections of ventral MCs has an excitatory net effect on dorsal GCs and further support our anatomical findings.…”

Section: Ventral Mcs Activity Is Required For Dorsal Gcs Activation Dmentioning

confidence: 72%

“…Given that only a partial ipsilateral population of dorsal MCs is labeled in our experiments, the high percentage (23.6 %) of labeled synapses on PV+ dendrites implies that the majority of excitatory inputs on these interneurons in the inner ML derive from dorsal MCs, and only a minor population from ventral MCs. Thus, ventral MCs may exert a net excitatory effect on dorsal GCs in contrast to the net inhibitory effect exerted by dorsal MCs (Bui et al, 2018;Hsu et al, 2016).…”

Section: Ventral Mcs Make Extensive Excitatory Synaptic Contacts Withmentioning

confidence: 96%

Novelty gates memory formation through ventro-dorsal hippocampal interaction

Fredes

Silva

Kobayashi

et al. 2019

Preprint

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Novelty facilitates formation of memories. The detection of novelty and storage of contextual memories are both mediated by the hippocampus, yet the mechanisms that link these two functions remain to be defined. Dentate granule cells (GCs) of the dorsal hippocampus fire upon novelty exposure forming engrams of contextual memory. However, their key excitatory inputs from the entorhinal cortex are not responsive to novelty and are insufficient to make dorsal GCs fire reliably. Here we uncover a powerful glutamatergic pathway to dorsal GCs from ventral hippocampal mossy cells (MCs) that relays novelty, and is necessary and sufficient for driving dorsal GCs activation. Furthermore, manipulation of ventral MCs activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MCs activity controls memory formation through an intra-hippocampal interaction mechanism gated by novelty.

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“…Our study suggests that MC loss in these conditions, even in a small number, could potentially lead to aberrant hippocampal neurogenesis and associated cognitive deficits. Furthermore, a recent study demonstrated that activation of remaining MCs after chronic temporal lobe epilepsy alleviates seizure severity; while inhibition of those MCs impairs cognitive functions (Bui et al, 2018). Therefore, targeting the MC circuit by enhancing the indirect pathway or dampening the direct pathway may constitute a therapeutic strategy to combat hippocampal hyperexcitability associated with various neurological disorders and brain injuries in order to preserve neural stem cell pool, maintain sustainable hippocampal neurogenesis, and promote cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways

Yeh

Asrican

Moss

et al. 2018

Neuron

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Summary Mossy cells (MCs) represent a major population of excitatory neurons in the adult dentate gyrus, a brain region where new neurons are generated from radial neural stem cells (rNSCs) throughout life. Little is known about the role of MCs in regulating rNSCs. Here we demonstrate that MC commissural projections structurally and functionally interact with rNSCs through both direct glutamatergic MC-rNSC pathway and indirect GABAergic MC-local interneuron-rNSC pathway. Specifically, moderate MC activation increases rNSC quiescence through dominant indirect pathway; while high MC activation increases rNSC activation through dominant direct pathway. In contrast, MC inhibition or ablation leads to a transient increase of rNSC activation, but rNSC depletion only occurs after chronic ablation of MCs. Together, our study identifies MCs as a critical stem cell niche component that dynamically controls adult NSC quiescence and maintenance under various MC activity states through a balance of direct glutamatergic and indirect GABAergic signaling onto rNSCs.

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Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory

Cited by 223 publications

References 32 publications

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

Novelty gates memory formation through ventro-dorsal hippocampal interaction

Mossy Cells Control Adult Neural Stem Cell Quiescence and Maintenance through a Dynamic Balance between Direct and Indirect Pathways

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