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Dentate Mossy Cell and Pattern Separation

Kazu Nakazawa1,*
1Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA


Three studies by Danielson et al. (2017), GoodSmith et al. (2017), and Senzai and Buzsaki (2017) distinguish
in vivo firing properties of dentate mossy cells from granule cells during behavior. Robust spatial remapping
of mossy cells, in contrast to sparse firing of granule cells, suggests differential involvement in pattern

A fundamental characteristic of an extracellular spikes (Henze and Buzsaki, tate spikes, (2) the difference in firing
episodic memory is the ability to minimize 2007), which may be detected in the rate between non-REM sleep and waking
interference between similar episodes. granule cell layer during in vivo recording. states, and (3) the unit waveform shape.
The dentate gyrus of the hippocampus is Furthermore, no in vivo neuronal firing Based on these criteria, they found that
widely viewed to accomplish this through properties of mossy cells in behaving most granule cells have no place field, or
a computation referred to as pattern sep- animals had previously been reported. just one, and only 6.6% of recorded cells
aration. This function is thought to alter Therefore, it was challenging to unambig- showed two or more. In contrast, 58% of
representation of input patterns from the uously resolve which firing patterns origi- mossy cells and 36% of CA3 pyramidal
entorhinal cortex to make them sparser nated from granule cells responsible for neurons had two or more place fields.
and less overlapping, thereby facilitating the pattern separation in vivo. Danielson et al. (2017) took a trans-hemi-
subsequent storage and retrieval of daily In the current issue of Neuron, three spheric viral labeling approach to selec-
episodes in area CA3. Granule cells, studies revealed in vivo firing properties tively label hilar mossy cells with the
which comprise the vast majority of the of granule cells and mossy cells in awake, Ca2+ indicator GCaMP6f, and conducted
cell population of the dentate, outnumber behaving rodent animals, each with the in vivo two-photon calcium imaging in
the inputs from entorhinal layer II neurons reliable method of distinguishing mossy awake, behaving mice. They found that
and do not communicate directly with cells from granule cells. GoodSmith et al. Ca2+ transients, a proxy for neuronal
each other. Due to this fan-out connec- (2017) identified rat granule cells and firing, are detected in mossy cells at
tion of the entorhinal-granule cell system, CA3 pyramidal cells based on detailed much higher rates with sufficient spatial
granule cells have been postulated as a histological identification of the position information but lower spatial tuning spec-
prime mediator of pattern separation. of recording electrodes, showing these ificity, when compared to granule cell
Indeed, only a small fraction (2%) of two cell types tend to have a single firing properties they recently reported (Daniel-
the rat granule cell population shows field in a single environment. In contrast, son et al., 2016). Taken together, these
experience-induced Arc gene expression mossy cells in the hilus tended to have three studies demonstrate that mossy
(Chawla et al., 2005). Granule-cell-spe- multiple firing fields and to fire in multiple cells fire frequently and have multiple
cific genetic ablation of NMDA receptors different environments. They reported place fields in different environments,
also reduces the ability to distinguish that only 9% of granule cells are active whereas granule cells exhibit extremely
two similar contexts in fear conditioning in a given environment, compared to sparse firing with only one place field
in mice (McHugh et al., 2007). However, 29% of CA3 neurons and 88% of mossy in an environment. These findings are
in vivo mechanisms for pattern separa- cells. Impressively, they also back up their consistent with the classical idea that
tion in the dentate remain far from delin- data with juxtacellular recording of a small sparse granule cell activity enhances
eated, presumably due to the lack of number of granule cells and hilar mossy pattern separation within the dentate.
a reliable method to identify and distin- cells for morphological identification, al- Some previous studies have reported
guish granule cells from other cell types, lowing them to confirm the very sparse different physiological features of granule
including glutamatergic mossy cells. firing of granule cells compared to mossy cells, including multiple place fields in
Located in the dentate hilar region, mossy cells. To go one step further, Senzai and an environment and promiscuous firing
cells receive convergent synaptic input Buzsaki (2017) attempted to establish in multiple environments. These features
mainly from dentate granule cells and objective physiological criteria for these resemble characteristics of mossy cells
local inhibitory interneurons, and send two cell types in mice from unbiased reported in the present studies, suggest-
associational and commissural axonal in vivo extracellular unit recording with ing that the previous reports may have
projections back to the granule cells and optogenetic validation. They identified included a mixed population of both
local interneurons along the longitudinal three main criteria to separate the excit- mossy and granule cells. Thus, the pre-
axis of the dentate gyrus. Curiously, atory neurons into granule cells and sent trio of studies makes an important
hilar mossy cells are known to be highly mossy cells: (1) location of the cell body contribution to the field by firmly estab-
excitable, generating large-amplitude relative to the reversal of the type 2 den- lishing the physiological firing features of

Neuron 93, February 8, 2017 2017 Elsevier Inc. 465



dentate mossy and granule cells in not. In Senzai and Buzsakis experiment, granule cell was silent. Considering its
behaving animals. only local, intra-chamber cues were high spike transmission probability, low
One obvious next question is whether altered and the room/chamber location probability of place field inheritance from
mossy cells are also involved in pattern was shared. In contrast, the rooms were granule to mossy cells is unexpected
separation. An active role for mossy cells changed in each recording in Good- and truly astonishing.
in pattern separation has been suggested Smiths experiment, which may have Where does this promiscuous activity
in previous experiments where specific introduced global remapping in the of the mossy cells come from? Based on
mossy cell loss caused transient granule granule cells. Although the reason granule the above results, it is tempting to specu-
cell hyperexcitability and impaired cells are less sensitive to local cues is un- late that other input sources rather than
contextual discrimination in Pavlovian clear, both groups speculate that granule granule cells are responsible for the
fear conditioning (Jinde et al., 2012). How- cells receive strong inputs from layer II en- place-related discharge of mossy cells.
ever, it remains to be investigated how torhinal cortex carrying head direction Indeed, there are several potential inputs
mossy and granule cells differentiate be- properties, which are known to be under to hilar mossy cells that might produce
tween distinct environments. One way to the control of distal cues (Knierim et al., multiple place fields in those cells. One
address this question is to assess the de- 1995). Thus, granule cells may be prefer- key candidate may be CA3 pyramidal
gree of remapping of their firing fields in entially anchored to the room locations cells (Figure 1). In particular, the ventral
response to environmental or contextual (global cues) by a static orientation of portion of CA3c pyramidal cells is known
change. GoodSmith et al. (2017) report the head direction system, resulting in to send massive axon collaterals to the hi-
most granule cells are active in only one minimal remapping despite exposure to lar region, making synapses with mossy
of four rooms, and, even if they fire in mul- novel local cues. Collectively, these pa- cells and local interneurons, but presum-
tiple rooms, there is little overlap of firing pers nicely demonstrate that mossy cell ably not granule cells (Scharfman, 2007).
rates. They conclude that granule cells remapping is more robust than that of Besides granule cells mossy fibers, CA3
use independent ensembles of cells granule cells, suggesting an instructive neurons also receive cortical inputs
to represent the environment, which is role of mossy cells in pattern separation. via entorhinal pyramidal neurons, which
again consistent with the classical idea Notably, this conclusion generates may provide the local cue information.
of pattern separation. In contrast, mossy novel and intriguing questions regarding Interestingly, Senzai and Buzsaki (2017)
cells are active in most environments, information flow within the dentate cir- show that the extent of spatial remapping
with individual neurons exhibiting a cuitry. How do mossy cells fire promiscu- is very similar between CA3 cells and
different spatial firing pattern in each envi- ously in response to external stimuli, mossy cells. Recent studies have also
ronment. They argue that mossy cells despite the rather sparse firing of pre- suggested an active involvement of
change the distribution of multiple firing synaptic granule cells? Mossy cells, as CA3c cells in pattern separation (Lee
fields for pattern separation. Danielson well as CA3 pyramidal cells, are known et al., 2015; Lu et al., 2015). Future study
et al. (2017) also compare the difference to receive highly effective detonator would be warranted to assess the place
in single-cell spatial tuning profiles by mossy fiber axons from the granule cells. cell inheritance from CA3c pyramidal cells
subjecting the animals to two sequential However, the remapping data, particu- to mossy cells. Another candidate might
exposures to either different or identical larly from the same room experiment, be semilunar granule cells (Figure 1),
contexts on the running belt. Although question the presumed idea that granule which are glutamatergic neurons located
spatial rate maps for both mossy and cells drive the mossy cells. Senzai and within the inner molecular layer (Williams
granule cells become less stable with Buzsaki (2017) go one step further, et al., 2007). Although semilunar granule
exposure to the different context (i.e., re- analyzing the in vivo spike transmission cells share some morphological traits
mapping), mossy cells exhibit stronger re- probability between granule cells and with granule cells, they appear to repre-
mapping of their firing fields than granule mossy cells, and confirm that granule to sent a distinct cell type. Importantly, this
cells. The differences in remapping mossy cell connectivity is high and poten- cell type, receiving input from the entorhi-
features among mossy, granule, and tiating during the burst stimuli. Therefore, nal cortex, is known to project to mossy
CA3 cells reported by Senzai and Buzsaki discharge of a single granule cell should cells, producing their persistent bursting
(2017) are more pronounced. They be sufficient to drive the target mossy activity (Larimer and Strowbridge, 2010).
examine the differences in spatial tuning cells. However, they also find that the Therefore, the semilunar granule cells
of dentate neurons when mice explore inheritance of spatial information from a may convey the entorhinal inputs to hilar
two contextually distinct chambers in the single granule cell to the interconnected mossy cells as an alternative route. A third
same room and find that granule cells mossy cells is extremely rare in the alternative is adult-born granule cells. No
remap much less than mossy cells or trial-to-trial comparison analysis in the studies have clarified in vivo neurophysio-
CA3 pyramidal cells. Some granule cells T-maze task. While granule cells have logical firing properties of adult-born
nicely preserve the place field centers in clear place fields, the downstream mono- granule cells with reliable cell type identi-
the two environments, which apparently synaptically connected mossy cells did fication. However, Danielson et al. (2016)
contradicts the remapping results by not inherit these fields in some cases. recently reported, using the same in vivo
GoodSmith et al. (2017). A key difference Conversely, in some pairs with overlap- Ca2+ imaging techniques as presented
between the two remapping experiments ping place fields, the postsynaptic mossy here, that adult-born granule cells exhibit
is whether the rooms were shared or cell was able to fire when its presynaptic higher activity and more diffuse firing

466 Neuron 93, February 8, 2017



mossy cells to granule cells is largely

mediated by feedforward inhibition. Alter-
natively, pattern separation for subtle
local cue discrimination may undergo
greater implementation in CA3c cells
when the granule cells differentiate the
global cues. In any case, further studies
are warranted to clarify the mechanisms
of pattern separation, particularly for
discrimination of local cues that may
mainly recruit mossy cells and CA3c cells.


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Figure 1. Schematic of Dentate Mossy Cell Circuitry
Despite the fact that mossy cells receive mossy fiber inputs from granule cells, projecting back to the Danielson, N.B., Turi, G.F., Ladow, M., and
granule cells, spatial representation between the two cell types appears to be independent (shown by Losonczy, A. (2017). Neuron 93, this issue,
dotted lines). Hypothetically, mossy cells may receive strong spatial information from CA3c pyramidal 552559.
cells and/or semilunar granule cells, both of which also receive entorhinal inputs. EC, entorhinal cortex;
GC, granule cell; MC, mossy cell; SGC, semilunar granule cell; IN, interneuron; PC, pyramidal cell; GCL, GoodSmith, D., Chen, X., Wang, C., Kim, S.H.,
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