An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

Botterill, Justin J.; Lu, Yi-Ling; LaFrancois, John; Bernstein, Hannah; Alcantara‐Gonzalez, David; Jain, Swati; Leary, Paige; Scharfman, Helen E.

doi:10.1016/j.celrep.2019.10.100

Cited by 72 publications

(121 citation statements)

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“…Our data suggest facilitation can occur during trains at beta frequency (25 Hz trains) and possibly theta frequency (5 Hz trains). These observations predict that the MC-GC synapses contribute to beta-associated information processing (including memory; Kay 2014) and possibly theta-associated spatial exploration, consistent with prior studies and discussion (Soltesz et al, 1993;GoodSmith et al, 2017;Hashimotodani et al, 2017;Senzai and Buzsaki, 2017;Bui et al, 2018;Botterill et al, 2019;Jung et al, 2019).…”

Section: Insight Gained From Multiple Optogenetic Stimulisupporting

confidence: 81%

“…During the onset of hyperexcitability accompanying acute trauma or seizures, GCs may depolarize, NMDA receptors become stronger, and GABAergic inhibition weaker or even excitatory (Lillis et al, 2012;Zhang et al, 2012). At this time, MCs appear to cause the GCs to become 'detonators' (Santhakumar et al, 2000;Botterill et al, 2019).…”

Section: When Would Weak MC Excitation Of Gcs Become Strong Enough Tomentioning

confidence: 99%

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Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice

Bernstein

Botterill

et al. 2020

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Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary cell type, granule cells (GCs), and GABAergic neurons which inhibit GCs. Prior studies suggest that the net effect of MCs is mainly to inhibit GCs, leading one to question why direct excitation of GCs is often missed. We hypothesized that MCs do have excitatory effects, but each GC is only excited weakly, at least under most experimental conditions. To address this hypothesis, MC axons were stimulated optogenetically in slices. A brief optogenetic stimulus to MC axons in the inner molecular layer (IML) led to a short-latency field EPSP (fEPSP) in the IML, suggesting there was a direct excitatory effect on GCs. Population spikes were negligible however, consistent with weak excitation. FEPSPs reflected AMPA/NMDA receptor-mediated EPSPs in GCs. EPSPs reached threshold after GC depolarization or facilitating NMDA receptors. GABAA and GABAB receptor-mediated IPSPs often followed EPSPs. At the network level, an conditions. This view is consistent with a network where there is selective activation of GCs, optimal for a function of the DG that has received much attention: pattern separation (Leutgeb et al.

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Section: Insight Gained From Multiple Optogenetic Stimulisupporting

confidence: 81%

Section: When Would Weak MC Excitation Of Gcs Become Strong Enough Tomentioning

confidence: 99%

Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice

Bernstein

Botterill

et al. 2020

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“…Importantly, electrophysiological studies from our lab (Botterill et al, 2019) and others (Yeh et al, 2018;Oh et al, 2019) have confirmed the excitatory and inhibitory effects of DREADDs in MCs. Control mice consisted of Drd2-Cre -/and Cre +/mice injected with a viral control fluorophore (mCherry).…”

Section: Experimental Design and Controlssupporting

confidence: 62%

“…To target MCs and their axons that span the septotemporal extent of the DG, virus was injected bilaterally into the rostral and caudal hippocampus as previously described (Botterill et al, 2019). Drd2-Cre +/mice were injected with eDREADDs (AAV2-hSyn-DIO-hM3D(Gq)-mCherry; ≥5x10 12 vg/mL, #44361, Addgene) or iDREADDs (AAV5-hSyn-DIO-hM4D(Gi)-mCherry; ≥8x10 12 vg/mL, #44362, Addgene; Figure 1A).…”

Section: Viral Targeting Of Mossy Cellsmentioning

confidence: 99%

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Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

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ABSTRACTThe dentate gyrus (DG) of the hippocampus is important for cognitive and affective behaviors. However, the circuits underlying these behaviors are unclear. DG mossy cells (MCs) have been a focus of attention because of their excitatory synapses on the primary DG cell type, granule cells (GCs). However, MCs also activate DG GABAergic neurons which inhibit GCs. We took advantage of specific methods and a gain- and loss-of function strategy with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to study MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENTThe dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

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Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

et al. 2021

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Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long‐range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre‐dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2‐Cre) and calcitonin receptor‐like receptor (Crlr‐Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long‐range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal–ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal–ventral differences in DG function.

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An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy

Cited by 72 publications

References 100 publications

Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice

Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

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