Author response: Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition

Yuan, Man; Meyer, Thomas; Benkowitz, Christoph; Savanthrapadian, Shakuntala; Ansel-Bollepalli, Laura; Foggetti, Angelica; Wulff, Peer; Alcamí, Pepe; Elgueta, Claudio; Bartos, Marlene

doi:10.7554/elife.21105.022

Cited by 5 publications

(10 citation statements)

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“…Indeed, inhibitory interneurons, putative PV cells, were identified by their fast spiking pattern and short spikes (39–41); whereas, excitatory neurons, putative granule cells and mossy cells, were recognised by their bursting pattern and slow spikes (39). Both neuronal populations increased their activity during laser stimulation, probably resulting from synaptic disinhibition (30), which was also consistent with the enhanced incidence of dentate spikes, a hallmark of dentate gyrus synchronous activity (45, 46). Low excitability of granule cells has been proposed as a requirement for efficient orthogonalization of afferent spiking patterns arising in the entorhinal cortex (27).…”

Section: Discussionsupporting

confidence: 67%

“…Furthermore, the regulation of orthogonalization of granule cells relies heavily on the perisomatic lateral inhibition provided by parvalbumin cells (83, 84). In turn, lateral inhibition might be controlled by SOM through direct dendritic inhibition of granule cells and perisomatic inhibition of parvalbumin cells (30). When mice explore novel environments, thus forming new memories, or during intense presynaptic activity in the dentate gyrus in vitro, dendritic inhibition is significantly larger than perisomatic inhibition (85, 86).…”

Section: Discussionmentioning

confidence: 99%

“…When mice explore novel environments, thus forming new memories, or during intense presynaptic activity in the dentate gyrus in vitro, dendritic inhibition is significantly larger than perisomatic inhibition (85, 86). A population of SOM locally innervates fast-spiking PV cells in the dentate gyrus and distally several other cell-types in the septum (30). Consistent with such anatomic connectivity, we found that inhibition of SOM increased the activity of putative PV neurons and granule cells.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, tonic inhibition of dentate gyrus granule cells is important for the control of memory interference (29). The most significant inhibitory inputs to granule cells arise locally from parvalbumin-expressing (PV) cells and somatostatin-expressing neurons (SOM) located mostly in the hilus (28, 30, 31). PV cells provide massive synaptic inhibition to the perisomatic region (32), whereas SOM directly innervate the dendritic arbor of granule cells.…”

Section: Introductionmentioning

confidence: 99%

“…PV cells provide massive synaptic inhibition to the perisomatic region (32), whereas SOM directly innervate the dendritic arbor of granule cells. Granule cell dendritic arborization is largely distributed across the molecular layer, and it is this region where entorhinal inputs massively impinge carrying contextual information (30). Recent experiments have changed the view about the modulatory function of SOM and established their control over the excitability of granule cells in vitro (33) and the size of neuronal ensembles during memory encoding in vivo (34).…”

Section: Introductionmentioning

confidence: 99%

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Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

Morales

Morici

Espinosa

et al. 2019

Preprint

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Episodic memory establishes and stores relations among the different elements of an experience, which are often similar and difficult to distinguish. Pattern separation, implemented by the dentate gyrus, is a neural mechanism that allows the discrimination of similar experiences by orthogonalizing synaptic inputs. Granule cells support such disambiguation by sparse rate coding, a process tightly controlled by highly diversified GABAergic neuronal populations, such as somatostatin-expressing cells which directly target the dendritic arbor of granule cells, massively innervated by entorhinal inputs reaching the molecular layer and conveying contextual information. Here, we tested the hypothesis that somatostatin neurons regulate the excitability of the dentate gyrus, thus controlling the efficacy of pattern separation during memory encoding in mice. Indeed, optogenetic suppression of dentate gyrus somatostatin neurons increased spiking activity in putative excitatory neurons and triggered dentate spikes. Moreover, optical inhibition of somatostatin neurons impaired both contextual and spatial discrimination of overlapping episodic-like memories during task acquisition. Importantly, effects were specific for similar environments, suggesting that pattern separation was selectively engaged when overlapping conditions ought to be distinguished. Overall, our results suggest that somatostatin cells regulate excitability in the dentate gyrus and are required for effective pattern separation during episodic memory encoding.Significance statementMemory systems must be able to discriminate stored representations of similar experiences in order to efficiently guide future decisions. This is solved by pattern separation, implemented in the dentate gyrus by granule cells to support episodic memory formation. The tonic inhibitory bombardment produced by multiple GABAergic cell populations maintains low activity levels in granule cells, permitting the process of pattern separation. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the dentate gyrus. Hence, somatostatin cells constitute an ideal candidate to regulate pattern separation. Here, by using optogenetic stimulation in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

Morales

Morici

Espinosa

et al. 2019

Preprint

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A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

Yao

Nguyen

Velthoven

et al. 2020

Preprint

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SUMMARYThe isocortex and hippocampal formation are two major structures in the mammalian brain that play critical roles in perception, cognition, emotion and learning. Both structures contain multiple regions, for many of which the cellular composition is still poorly understood. In this study, we used two complementary single-cell RNA-sequencing approaches, SMART-Seq and 10x, to profile ∼1.2 million cells covering all regions in the adult mouse isocortex and hippocampal formation, and derived a cell type taxonomy comprising 379 transcriptomic types. The completeness of coverage enabled us to define gene expression variations across the entire spatial landscape without significant gaps. We found that cell types are organized in a hierarchical manner and exhibit varying degrees of discrete or continuous relatedness with each other. Such molecular relationships correlate strongly with the spatial distribution patterns of the cell types, which can be region-specific, or shared across multiple regions, or part of one or more gradients along with other cell types. Glutamatergic neuron types have much greater diversity than GABAergic neuron types, both molecularly and spatially, and they define regional identities as well as inter-region relationships. For example, we found that glutamatergic cell types between the isocortex and hippocampal formation are highly distinct from each other yet possess shared molecular signatures and corresponding layer specificities, indicating their homologous relationships. Overall, our study establishes a molecular architecture of the mammalian isocortex and hippocampal formation for the first time, and begins to shed light on its underlying relationship with the development, evolution, connectivity and function of these two brain structures.

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Integrative single-nucleus multi-omics analysis prioritizes candidatecisandtransregulatory networks and their target genes in Alzheimer’s disease brains

Gamache

Gingerich

Shwab

et al. 2023

Preprint

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BackgroundThe genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.MethodsHere, we present the largestparallelsingle-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) andcisco-accessibility networks (CCANs).ResultsIntegrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype specific candidatecisregulatory elements (cCREs), their candidate target genes, andtrans-interacting transcription factors (TFs), some of which were LOAD-DEG, for example,ELK1in excitatory neurons (Exc1) andKLF13andJUN, found in multiple cell subtypes. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs including,APOEandMYO1Ein a specific subtype of microglia andBIN1in a subpopulation of oligodendrocytes.ConclusionsTo our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings revealed crosstalk between epigenetic, genomic, and transcriptomic determinates of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specificcis-transinteractions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.

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Author response: Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition

Cited by 5 publications

References 0 publications

Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

Integrative single-nucleus multi-omics analysis prioritizes candidatecisandtransregulatory networks and their target genes in Alzheimer’s disease brains

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