Review
doi: 10.1038/nrn.2016.87. Epub 2016 Jul 28.The enigmatic mossy cell of the dentate gyrus
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- PMID:27466143
- PMCID: PMC5369357
- DOI: 10.1038/nrn.2016.87
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Review
The enigmatic mossy cell of the dentate gyrus
Helen E Scharfman. Nat Rev Neurosci.2016 Sep.
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Abstract
Mossy cells comprise a large fraction of the cells in the hippocampal dentate gyrus, suggesting that their function in this region is important. They are vulnerable to ischaemia, traumatic brain injury and seizures, and their loss could contribute to dentate gyrus dysfunction in such conditions. Mossy cell function has been unclear because these cells innervate both glutamatergic and GABAergic neurons within the dentate gyrus, contributing to a complex circuitry. It has also been difficult to directly and selectively manipulate mossy cells to study their function. In light of the new data generated using methods to preferentially eliminate or activate mossy cells in mice, it is timely to ask whether mossy cells have become any less enigmatic than they were in the past.
Conflict of interest statement
The author declares no competing interests.
Figures
a | The general organization of the dentate gyrus in the coronal and horizontal planes of the rodent brain. The area surrounded by the dashed box is expanded in the inset figure to show the laminar organization of the dentate gyrus, which is composed of a molecular layer (MOL), granule cell layer (GCL) and hilus (HIL). The GCL contains the principal cells of the dentate gyrus, the granule cells. The dendrites of the granule cells extend into the MOL, and their axons traverse the HIL and terminate in area CA3c.b | A schematic of the primate dentate gyrus shows that it is similar to that of the rodents, but that there is gyrification. In addition, CA3c is larger in primates than in rodents and includes a reflected blade (indicated by the arrowhead).c | The layers of the dentate gyrus are shown. The sources of major afferent inputs are shown on the right (red box indicates the GABAergic input and grey boxes indicate inputs from other neurotransmitters). GABAergic interneurons innervate all layers. The lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC) innervate the outer molecular layer (OML) and the middle molecular layer (MML), respectively. Supramammillary (Mamm), cholinergic, mossy cell and ventral CA3 (vCA3) pyramidal cell axons innervate the inner molecular layer (IML). The OML and MML also receive inputs from the brainstem (including noradrenergic and 5-hydroxytryptamine (5-HT; also known as serotonin) inputs) and from basal forebrain cholinergic neurons. The HIL receives diverse inputs, including the axons of granule cells, dentate gyrus GABAergic neurons, mossy cells, CA3 pyramidal cells, neuromodulatory inputs from the brainstem (such as noradrenaline (NA), 5-HT and dopamine (DA)) and basal forebrain cholinergic neurons,,,,. The efferents from the dentate gyrus to other areas arise mainly from granule cells that project to the HIL and CA3. The granule cell axon, called a mossy fibre, is complex. It makes giant boutons that innervate thorny excrescences of mossy cells and pyramidal cells and small boutons that arise from hilar collaterals and filamentous extensions from the giant boutons,,,,. The small boutons primarily contact interneurons but also form contacts on distal dendrites of mossy cells,. ACh, acetylcholine; F, fissure; SGZ, subgranular zone.
a | Glutamatergic cells of the dentate gyrus include granule cells and mossy cells. Granule cells are not only located in the granule cell layer (GCL); there are small subsets in the inner molecular layer (IML) and hilus (HIL), and precursors to granule cells are located in the subgranular zone (SGZ). Mossy cells have long dendrites, some of which extend into the molecular layer (MOL; comprised of the IML, middle molecular layer (MML) and outer molecular layer (OML)),.b | GABAergic neurons of the dentate gyrus are heterogeneous. Their nomenclature is based on the location of the cell body and the axon terminal field–. For example, MOPP cells have a cell body in the MOL and terminals in the OML and MML, where the terminals of the perforant path are located–. HICAP cells (interneurons with a hilar cell body with axon targeting the commissural/associational pathway) innervate the IML, where the commissural/associational projection from mossy cells is located–. The neurons that innervate the granule cell somata or the axon initial segments are called perisomatic-targeting cells. Two of the most common cell types in this group are basket cells, which make basket-like endings around the granule cells and often have a pyramidal-shaped soma that is located at the border of the GCL and HIL, and axo-axonic (AA) cells–. AA cells are often present near or in the GCL, as shown, and innervate granule cell axon initial segments–. Several GABAergic neuron subtypes innervate granule cell dendrites. The most common of these are cells in the HIL that innervate the OML and MML (HIPP cells, hilar cells that project to the terminal zone of the perforant path). An example of a neurogliaform cell (NG) that innervates the molecular layer is shown. There are some types of GABAergic neurons that have an axon that innervates more than one layer (here labelled ‘other’),, and some interneurons innervate each other, such as calretinin-expressing hilar cells (CR).c | The upper image shows an example of a biocytin-filled mossy cell with thorny excrescences labelled in the higher magnification inset (indicated by the arrows). The lower image shows an interneuron that was filled with biocytin in a rat hippocampal slice. Arrows point to primary dendrites that are smooth relative to the mossy cell. F, fissure.
a | The axon of a single ventral mossy cell is illustrated schematically. Near the soma, the local ipsilateral branches of the mossy cell axon make synapses in the hilus (HIL) and the inner molecular layer (IML),,. Far from the soma, the distant ipsilateral or distant contralateral branches of the axon project primarily to the IML–,,,.b | Distant and local ipsilateral circuitry. At distant ipsilateral locations, the axon primarily makes synapses on spines; because there are few spines on dentate gyrus interneurons, it is likely that the mossy cell axon in the IML innervates granule cells. In addition, the mossy cell axon extends hilar, outer molecular layer (OML) and middle molecular layer (MML) collaterals,,. It is not clear whether mossy cell terminals in the OML and MML make synapses, or what cell types mossy cells target in the HIL (indicated by question marks). At local ipsilateral locations, the mossy cell axons collateralize in the HIL, especially near the soma. There, they are likely to contact interneurons because of the numerous interneuron dendrites present in this region and the absence of granule cell dendrites. Mossy cells also make local projections to the IML, but these are not as numerous as those to distant sites. GCL, granule cell layer; SGZ, subgranular zone.
a | A long-standing proposal is that mossy cells link subsets of granule cells that are spatially separated and therefore facilitate associative learning.b | Another long-standing view is that granule cells primarily activate GABAergic interneurons, particularly basket cells,. This could lead to a possible circuit, as shown, in which mossy cells amplify the normal feedback inhibition of granule cells by activating GABAergic interneurons. In the figure, this circuit is exemplified by the perforant path (PP)-mediated depolarization of a granule cell. If the depolarization evokes an action potential, the granule cell would subsequently depolarize a basket cell that innervates numerous granule cells (only one granule cell is depicted), increasing the inhibition of granule cells. On the right, this physiology is schematized. Without the mossy cell in the circuit (top), a PP input (indicated by the arrow) elicits an excitatory postsynaptic potential (EPSP) in the granule cell. The EPSP is followed by an inhibitory postsynaptic potential (IPSP) that reflects the feedback inhibition (that is, the activation of the basket cell by the granule cell, which in turn hyperpolarizes the granule cell). Notably, it is unclear whether basket cells innervate the same granule cells that activate them; the circuit in the diagram is simplified for clarity. With the mossy cell in the circuit (bottom), the PP input elicits an EPSP followed by a larger and longer IPSP in the granule cell because mossy cells are first depolarized by granule cells and then activate basket cells. Note that if the PP directly innervates basket cells and mossy cells, this would lead to feedforward inhibition of granule cells.c | According to another hypothesis, the excitatory effects of mossy cells depolarize granule cells only under some conditions. In this example, the effects of a CA3 pyramidal cell input to a granule cell depend on the presence or absence of concurrent cholinergic input. Without the cholinergic input, CA3 pyramidal cells will primarily hyperpolarize granule cells by activating interneurons. With cholinergic input mediated by acetylcholine (ACh), which preferentially suppresses the interneurons, CA3 pyramidal cells will primarily depolarize granule cells by activating mossy cells,. The schematic includes several simplifications for clarity. For example, the cholinergic input to pyramidal cells and mossy cells is not shown. In addition, the cholinergic input depolarizes mossy cells, which would lead to a greater potential to excite granule cells in the circuit that is shown.d | Finally, mossy cells have also been proposed to act as ‘sentinels’ that inform granule cells that changes have occurred even in the absence of strong PP input. This sentinel function would be reflected by the lack of a response of a granule cell to the PP input unless the mossy cell is activated. This might occur, for example, if the PP input to granule cells is weak. Under these conditions, the PP might still activate semilunar granule cells because they are activated more readily by the PP. These cells have a robust excitatory effect on mossy cells,, which would then activate granule cells, as shown in the diagram. On the right, this is depicted by a lack of depolarization in a granule cell (located in the granule cell layer (GCL)) in the absence of mossy cells. HIL, hilus; IML, inner molecular layer; MML, middle molecular layer; OML, outer molecular layer; SGZ, subgranular zone.
References
- Jinde S, et al. Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation. Neuron. 2012;76:1189–1200. This study examined the consequence of ablating mossy cells with the most selective approach to date. Although some CA3 pyramidal cells were also affected, the results showed that mossy cells have an important role in the dentate gyrus network. - PMC - PubMed
- Hsu TT, Lee CT, Tai MH, Lien CC. Differential recruitment of dentate gyrus interneuron types by commissural versus perforant pathways. Cereb Cortex. 2016;26:2715–2727. This study used optogenetics in hippocampal slices to show that mossy cells could excite or inhibit granule cells; the authors found that the major effect was inhibition. - PubMed
- Steward O, Scoville SA. Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat. J Comp Neurol. 1976;169:347–370. - PubMed
- Witter MP. The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog Brain Res. 2007;163:43–61. - PubMed
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