Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment

Oh, Seo Jin; Cheng, Jia; Jang, Jin-Wook; Arace, Jeffrey; Jeong, Minseok; Shin, Chang-Hoon; Park, Jeongrak; Jin, Junghee; Greengard, Paul; Oh, Yong‐Seok

doi:10.1038/s41380-019-0384-6

Cited by 44 publications

(50 citation statements)

References 56 publications

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“…Viral expression in Drd2-Cre +/mice was characterized by large hilar mCherry + cells proximal to the injection site and a dense band of mCherry + labeling in the inner molecular layer (IML) throughout the septotemporal axis of the DG, consistent with the location of MCs and their major axon projection ( Figure 1C-D; Scharfman, 2016). The pattern of viral expression has been validated in previous work by our laboratory (Botterill et al, 2019;Bernstein et al, 2020) and confirmed by others (Danielson et al, 2017;Bui et al, 2018;Yeh et al, 2018;Azevedo et al, 2019;Oh et al, 2019).…”

Section: Viral Expressionsupporting

confidence: 80%

“…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: 59%

“…Importantly, MCs in dorsal DG project to ventral DG (Scharfman, 2016). Also, MCs appear to have a role in depression (Oh et al, 2019) which usually occurs with anxiety. MCs express genes that are linked to schizophrenia (Scharfman and Bernstein, 2015;Yuan et al, 2015), which is a disease with anxiety (Temmingh and Stein, 2015).…”

Section: Mcs Influence Anxiety-like Behaviorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Part of this uncertainty is due to conflicting reports about MCs in anxiety-like behaviors from previous studies (Jinde et al, 2012;Bui et al, 2018;Oh et al, 2019), possibly attributable to the different methods in targeting and manipulating MCs. In addition, the majority of MC studies to date have focused on male subjects (Jinde et al, 2012;Duffy et al, 2013;Moretto et al, 2017;Senzai and Buzsaki, 2017;Oh et al, 2019) or did not provide a clear view of sex differences (Danielson et al, 2017;GoodSmith et al, 2017;Bui et al, 2018). The focus on male subjects is problematic because there are known sex differences in GC structure, activity and synaptic plasticity (Hajszan et al, 2007;Zitman and Richter-Levin, 2013;Harte-Hargrove et al, 2015;Yagi and Galea, 2019) and some data showing sex differences in MCs (Guidi et al, 2006).…”

Section: Introductionmentioning

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

Preprint

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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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Section: Viral Expressionsupporting

confidence: 80%

Section: Experimental Design and Controlssupporting

confidence: 59%

Section: Mcs Influence Anxiety-like Behaviorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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

Preprint

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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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Activin A regulates the excitability of hippocampal mossy cells

2022

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Mossy cells (MCs) in the hilus of the dentate gyrus (DG) receive increasing attention as a major player controlling information processing in the DG network. Furthermore, disturbed MC activity has been implicated in widespread neuropsychiatric disorders such as epilepsy and major depression. Using whole‐cell patch‐clamp recordings from MCs in acute hippocampal slices from wild type and transgenic mice, we demonstrate that activin, a member of the transforming growth factor‐β (TGF‐β) family, has a strong neuromodulatory effect on MC activity. Disruption of activin receptor signaling reduced MC firing, dampened their excitatory input and augmented their inhibitory input. By contrast, acute application of recombinant activin A strongly increased MC activity and promoted excitatory synaptic drive. Notably, similar changes of MC activity have been observed in a rodent model of depression and after antidepressant drug therapy, respectively. Given that a rise in activin signaling particularly in the DG has been proposed as a mechanism of antidepressant action, our data suggest that the effect of activin on MC excitability might make a considerable contribution in this regard.

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Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment

Cited by 44 publications

References 56 publications

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

Activin A regulates the excitability of hippocampal mossy cells

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