-
The Journal of Neuroscience : the... Apr 2022Mossy cells (MCs) of the dentate gyrus are key components of an excitatory associative circuit established by reciprocal connections with dentate granule cells (GCs)....
Mossy cells (MCs) of the dentate gyrus are key components of an excitatory associative circuit established by reciprocal connections with dentate granule cells (GCs). MCs are implicated in place field encoding, pattern separation, and novelty detection, as well as in brain disorders such as temporal lobe epilepsy and depression. Despite their functional relevance, little is known about the determinants that control MC activity. Here, we examined whether MCs express functional kainate receptors (KARs), a subtype of glutamate receptors involved in neuronal development, synaptic transmission, and epilepsy. Using mouse hippocampal slices, we found that bath application of submicromolar and micromolar concentrations of the KAR agonist kainic acid induced inward currents and robust MC firing. These effects were abolished in GluK2 KO mice, indicating the presence of functional GluK2-containing KARs in MCs. In contrast to CA3 pyramidal cells, which are structurally and functionally similar to MCs and express synaptic KARs at mossy fiber (MF) inputs (i.e., GC axons), we found no evidence for KAR-mediated transmission at MF-MC synapses, indicating that most KARs at MCs are extrasynaptic. Immunofluorescence and immunoelectron microscopy analyses confirmed the extrasynaptic localization of GluK2-containing KARs in MCs. Finally, blocking glutamate transporters, a manipulation that increases extracellular levels of endogenous glutamate, was sufficient to induce KAR-mediated inward currents in MCs, suggesting that MC-KARs can be activated by increases in ambient glutamate. Our findings provide the first direct evidence of functional extrasynaptic KARs at a critical excitatory neuron of the hippocampus. Hilar mossy cells (MCs) are an understudied population of hippocampal neurons that form an excitatory loop with dentate granule cells. MCs have been implicated in pattern separation, spatial navigation, and epilepsy. Despite their importance in hippocampal function and disease, little is known about how MC activity is recruited. Here, we show for the first time that MCs express extrasynaptic kainate receptors (KARs), a subtype of glutamate receptors critically involved in neuronal function and epilepsy. While we found no evidence for synaptic KARs in MCs, KAR activation induced strong action potential firing of MCs, raising the possibility that extracellular KARs regulate MC excitability and may also promote dentate gyrus hyperexcitability and epileptogenesis.
Topics: Animals; Glutamic Acid; Kainic Acid; Mice; Mossy Fibers, Hippocampal; Pyramidal Cells; Receptors, Kainic Acid; Synapses
PubMed: 35197316
DOI: 10.1523/JNEUROSCI.0922-21.2022 -
Neurobiology of Disease Nov 2023Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth...
Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system.
Topics: Animals; Humans; Mice; Dentate Gyrus; Epilepsy; Epilepsy, Temporal Lobe; Methyl-CpG-Binding Protein 2; MicroRNAs; Mossy Fibers, Hippocampal; TOR Serine-Threonine Kinases
PubMed: 37931884
DOI: 10.1016/j.nbd.2023.106346 -
Cell Reports Dec 2021Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes,...
Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV) and somatostatin-expressing (SST), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV and SST interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST interneurons has the opposite effect. Thus, DG and CA3 PV and SST interneurons bidirectionally modulate the flow of information through the hippocampal circuit.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Entorhinal Cortex; Female; GABAergic Neurons; Interneurons; Male; Mice; Mice, Inbred C57BL; Somatostatin
PubMed: 34965435
DOI: 10.1016/j.celrep.2021.110159 -
Cell Reports Aug 2021Mouse hippocampus CA1 place-cell discharge typically encodes current location, but during slow gamma dominance (SG), when SG oscillations (30-50 Hz) dominate...
Mouse hippocampus CA1 place-cell discharge typically encodes current location, but during slow gamma dominance (SG), when SG oscillations (30-50 Hz) dominate mid-frequency gamma oscillations (70-90 Hz) in CA1 local field potentials, CA1 discharge switches to represent distant recollected locations. We report that dentate spike type 2 (DS) events initiated by medial entorhinal cortex II (MECII)→ dentate gyrus (DG) inputs promote SG and change excitation-inhibition coordinated discharge in DG, CA3, and CA1, whereas type 1 (DS) events initiated by lateral entorhinal cortex II (LECII)→DG inputs do not. Just before SG, LECII-originating SG oscillations in DG and CA3-originating SG oscillations in CA1 phase and frequency synchronize at the DS peak when discharge within DG and CA3 increases to promote excitation-inhibition cofiring within and across the DG→CA3→CA1 pathway. This optimizes discharge for the 5-10 ms DG-to-CA1 neuro-transmission that SG initiates. DS properties identify extrahippocampal control of SG and a cortico-hippocampal mechanism that switches between memory-related modes of information processing.
Topics: Action Potentials; Animals; Behavior, Animal; Biomarkers; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Gamma Rhythm; Hippocampus; Memory; Mice, Inbred C57BL; Perforant Pathway; Signal Transduction; Mice
PubMed: 34348165
DOI: 10.1016/j.celrep.2021.109497 -
Neuroscience Letters Jan 2022The adult dentate gyrus (DG) of the hippocampal formation is a specialized region of the brain that creates new adult-born neurons from a pool of resident adult neural... (Review)
Review
The adult dentate gyrus (DG) of the hippocampal formation is a specialized region of the brain that creates new adult-born neurons from a pool of resident adult neural stem and progenitor cells (aNSPCs) throughout life. These aNSPCs undergo epigenetic and epitranscriptomic regulation, including 3D genome interactions, histone modifications, DNA modifications, noncoding RNA mechanisms, and RNA modifications, to precisely control the neurogenic process. Furthermore, the specialized neurogenic niche also uses epigenetic mechanisms in mature neurons and glial cells to communicate signals to direct the behavior of the aNSPCs. Here, we review recent advances of epigenetic regulation in aNSPCs and their surrounding niche cells within the adult DG.
Topics: Adult Stem Cells; Animals; Dentate Gyrus; Epigenesis, Genetic; Humans; Neural Stem Cells; Neurogenesis; Stem Cell Niche
PubMed: 34774980
DOI: 10.1016/j.neulet.2021.136343 -
Journal of Healthcare Engineering 2021As an important part of the brain, the dentate gyrus has an irreplaceable effect in the process of memory generation. Therefore, the study of the dentate gyrus model has...
As an important part of the brain, the dentate gyrus has an irreplaceable effect in the process of memory generation. Therefore, the study of the dentate gyrus model has important significance in the study of brain function. This paper, combined with the real anatomical structure of the dentate gyrus, is based on the existing calculation model for studying the pathological state of the dentate gyrus, a network model of dentate gyrus based on bionics. Then, a simulation experiment on the normal dentate gyrus model is performed on the NEURON platform, the output of each neuron in the model is observed, and a conclusion that the improved model can respond to stimuli, generate action potentials, and transmit them along with the neural network is made. At the same time, the output results are compared with the existing pathological models, and the characteristics of the stimulus response between neurons in the dentate gyrus under normal physiological conditions are obtained. Finally, according to the semiquantitative classification definition and quantitative classification definition of the small-world network, the model is analyzed, and it is concluded that the improved dentate gyrus network model has small-world characteristics. Therefore, the neurons in the improved dentate gyrus model are tightly connected and can simulate the real dentate gyrus to a certain extent.
Topics: Bionics; Dentate Gyrus; Humans
PubMed: 34912532
DOI: 10.1155/2021/4609741 -
Current Biology : CB Feb 2023Stable neural ensembles are often thought to underlie stable learned behaviors and memory. Recent longitudinal experiments, however, that tracked the activity of the...
Stable neural ensembles are often thought to underlie stable learned behaviors and memory. Recent longitudinal experiments, however, that tracked the activity of the same neurons over days to weeks have shown that neuronal activity patterns can change over extended timescales even if behaviors remain the same - a phenomenon termed representational drift. We have tested whether neural circuit remodeling, defined as any change in structural connectivity, contributes to representational drift. To do this, we tracked how hippocampal CA1 spatial representations of a familiar environment change with time in conventionally housed mice relative to mice housed with a running wheel. Voluntary exercise is an environmental stimulus that promotes hippocampal circuit remodeling, primarily via promoting adult neurogenesis in the dentate gyrus. Adult neurogenesis alters structural connectivity patterns, as the integration of adult-generated granule cells (abGCs) is a competitive process where new input-output synaptic connections may co-exist and/or even replace existing synaptic connections. Comparing the spatial activity of downstream hippocampal CA1 place cells in the same familiar environment over two weeks, we found that the activity of place cells in exercise mice exhibited accelerated representational drift compared to control mice, suggesting that hippocampal circuit remodeling may indeed drive representational drift.
Topics: Mice; Animals; Place Cells; Neurons; Hippocampus; Neurogenesis; Dentate Gyrus; Mice, Inbred C57BL
PubMed: 36750030
DOI: 10.1016/j.cub.2022.12.033 -
Proceedings of the National Academy of... Oct 2022High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples...
High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples support memory retrieval. However, it is unclear if ripples signal the reinstatement of episodic memories. Analyzing electrophysiological MTL recordings from 245 neurosurgical participants performing episodic recall tasks, we find that the rate of hippocampal ripples rises just prior to the free recall of recently formed memories. This prerecall ripple effect (PRE) is stronger in the CA1 and CA3/dentate gyrus (CA3/DG) subfields of the hippocampus than the neighboring MTL regions entorhinal and parahippocampal cortex. PRE is also stronger prior to the retrieval of temporally and semantically clustered, as compared with unclustered, recalls, indicating the involvement of ripples in contextual reinstatement, which is a hallmark of episodic memory.
Topics: CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Humans; Magnetic Resonance Imaging; Memory, Episodic; Mental Recall; Temporal Lobe
PubMed: 36161912
DOI: 10.1073/pnas.2201657119 -
Nature Neuroscience Sep 2021Cortical and subcortical circuitry are thought to play distinct roles in the generation of sleep oscillations and global state control, respectively. Here we silenced a...
Cortical and subcortical circuitry are thought to play distinct roles in the generation of sleep oscillations and global state control, respectively. Here we silenced a subset of neocortical layer 5 pyramidal and archicortical dentate gyrus granule cells in male mice by ablating SNAP25. This markedly increased wakefulness and reduced rebound of electroencephalographic slow-wave activity after sleep deprivation, suggesting a role for the cortex in both vigilance state control and sleep homeostasis.
Topics: Animals; Dentate Gyrus; Male; Mice; Mice, Transgenic; Neocortex; Neurons; Sleep; Synaptosomal-Associated Protein 25; Wakefulness
PubMed: 34341585
DOI: 10.1038/s41593-021-00894-6 -
The EMBO Journal Nov 2023For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental... (Review)
Review
For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above-mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into "supra-pyramidal" and "infra-pyramidal". Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.
Topics: Animals; Dentate Gyrus; Hippocampus; Neurons; Learning; Memory; Neurogenesis; Mammals
PubMed: 37743770
DOI: 10.15252/embj.2023113524