Download Synapses formed by normal and abnormal hippocampal mossy fibers

Cell Tissue Res
DOI 10.1007/s00441-006-0269-2
REVIEW
Synapses formed by normal and abnormal hippocampal
mossy fibers
Michael Frotscher & Peter Jonas & Robert S. Sloviter
Received: 15 May 2006 / Accepted: 31 May 2006
# Springer-Verlag 2006
Abstract The axon terminals (mossy fibers) of hippocampal
dentate granule cells form characteristic synaptic connections
with large spines or excrescences of both hilar mossy cells
and CA3 pyramidal neurons. Interneurons of the hilar region
and area CA3 are also prominent targets of mossy fibers.
The tracing of biocytin-filled mossy fibers and immunolabeling of target cells with interneuron markers has revealed
that the majority of mossy fiber synapses project to γ
aminobutyric acid (GABA)-ergic inhibitory interneurons
rather than to excitatory principal cells, although the
functional implications of these quantitative differences are
unclear. Following a brief description of the “classical”
mossy fiber synapse on excrescences of CA3 pyramidal
cells, the present review focuses on the contacts formed
between granule cells and GABAergic interneurons, both
normally and after synaptic reorganization. In response to
deafferentation of mossy cell target cells, which include both
granule cells and interneurons, mossy fibers “sprout” new
axon collaterals that form a band of supragranular mossy
The work at the authors’ laboratories is supported by the Deutsche
Forschungsgemeinschaft (Transregio Sonderforschungsbereich TR-3,
to M.F.), and NIH-NINDS (grant no. NS 18201, to R.S.S.). We thank
Sigrun Nestel for excellent technical assistance.
M. Frotscher (*)
Institut für Anatomie und Zellbiologie und Zentrum für
Neurowissenschaften, Albert-Ludwigs-Universität Freiburg,
79104 Freiburg, Germany
e-mail: [email protected]
P. Jonas
Physiologisches Institut, Albert-Ludwigs-Universität Freiburg,
79104 Freiburg, Germany
R. S. Sloviter
Departments of Pharmacology and Neurology,
University of Arizona College of Medicine,
Tucson, AZ 85724, USA
fibers in the inner molecular layer of the dentate gyrus.
Although most newly formed recurrent mossy fibers
establish synapses with granule cells, there is an apparently
convergent input of new mossy fibers onto GABA-immunoreactive interneuron dendrites that traverse the inner
molecular layer. These mossy fiber-interneuron synapses in
the dentate gyrus are observed in chronically epileptic rats
and may be the structural correlate of the granule cell
hyperinhibition observed in these animals in vivo. Together,
the findings reviewed here establish mossy fiber synapses as
an important component of inhibitory circuits in the
hippocampus.
Keywords Mossy fiber synapse . CA3 pyramidal cells .
Dentate gyrus granule cells . Hippocampal interneurons .
Mossy cells . Mossy fiber sprouting
Introduction
The granule cells of the hippocampal dentate gyrus are
perhaps the most unusual neuronal population of the brain.
Granule cells are highly conserved across species (Seress
and Frotscher 1990) and are born continuously throughout
life, a characteristic that may be related to their role in
memory formation (Schmidt-Hieber et al. 2004). Remarkably, granule cells constitutively express both excitatory and
inhibitory small amino acid transmitters, viz., glutamate and γ
aminobutyric acid (GABA; Sloviter et al. 1996). Although
granule cells are relatively resistant to a variety of neurological insults (Nadler et al. 1978), they are exquisitely and
selectively vulnerable to the absence of circulating adrenal
hormones (Sloviter et al. 1989). Dentate granule cells are
bipolar neurons with dendrites that extend into the molecular
layer and with axons that enter the hilar region from the
Cell Tissue Res
opposite pole of the cell body. In this way, a clear segregation of the input side from the output side is established,
an organization that is altered in human epilepsy and animal
models of the disorder (see below). The afferent input to the
granule cells is clearly segregated, with fibers from the
lateral and medial entorhinal cortex terminating in the outer
molecular layer on distal granule cell dendrites, and
commissural/associational fibers originating from hilar
mossy cells forming synapses on proximal dendrites in the
inner molecular layer (Blackstad 1956, 1958; Förster et al.
2006). Granule cells thus receive both cortical and hippocampal internal input in a clearly segregated manner. The
thin unmyelinated axon of the granule cell (the mossy fiber)
forms various types of presynaptic bouton that establish
characteristic synaptic contacts with a variety of postsynaptic
target cells.
In the present review, we will address these different types
of synapses and emphasize the synaptic connections that
mossy fibers form with GABAergic inhibitory interneurons
under normal and pathological conditions. Traditionally, the
mossy fiber synapses with CA3 pyramidal neurons are
viewed as the main granule cell output connection, forming
the second synapse in the trisynaptic excitatory pathway of
the hippocampal formation (Andersen et al. 1971). This view
was based on early Golgi studies (Golgi 1886; Koelliker
1896; Ramón y Cajal 1911) and electron-microscopic analyses of the mossy fiber termination zone (Blackstad and
Kjaerheim 1961; Hamlyn 1962). In Golgi preparations, these
authors noticed that the thin mossy fiber axon gave rise to
large en passant swellings and terminal expansions, which
turned out to be giant mossy fiber boutons as seen by
electron microscopy (EM). These presynaptic swellings
resembled moss on trees and were therefore called “mossy
fibers” by Ramón y Cajal (1911). Similarly large in size are
the specialized postsynaptic elements, viz., the thorny
excrescences, on proximal dendritic portions of CA3
pyramidal cells and large hilar neurons, with the latter being
called mossy cells for the same reason (Amaral 1978).
Mossy fibers stop at the border to CA1, and CA1 pyramidal
cells lack thorny excrescences, as do the dendrites of
GABAergic inhibitory interneurons. Thus, neither CA1
pyramidal cells nor GABAergic interneurons were thought
to receive granule cell input via these highly specialized
synapses (Lorente de Nó 1934).
In recent years, a more complex picture of the synapses
formed by granule cell axons has emerged. With the advent
of new neuroanatomical techniques, the study of single
identified neurons by EM and the characterization of their
specific synaptic connections have become possible. Thus,
the labeling of GABAergic interneurons, either by means of
the Golgi/EM technique or by immunostaining, has shown
that these cells are also targets of hippocampal mossy fibers
(Frotscher 1985, 1989; Leranth and Frotscher 1986; Deller
and Leranth 1990; Acsády et al. 1998). Following a brief
description of the “classical” mossy fiber synapses on CA3
pyramidal neurons, we will focus, in this review, on the
synapses of granule cell axons with GABAergic interneurons
under normal conditions and in chronic epileptic rats that
show mossy fiber sprouting.
Mossy fiber synapses on CA3 pyramidal neurons
Thin sectioning of a Golgi-impregnated gold-toned terminal
expansion of a mossy fiber axon for EM has revealed the
characteristics of this specialized synapse (Fig. 1a). The
gold-labeled identified bouton is large when compared with
other types of presynaptic cortical bouton. It is densely filled
with clear synaptic vesicles, with a few intermingled densecore vesicles. Numerous asymmetric synaptic contacts are
established with the complex spines of the postsynaptic
pyramidal cell protruding deeply into the presynaptic
bouton. Chicurel and Harris (1992) have found 37 such
contacts in a serially reconstructed mossy fiber bouton.
Asymmetric synaptic contacts are rarely observed on
dendritic shafts, and these shaft synapses are likely to be
mossy fiber to interneuron synaptic contacts (see below).
Other contacts, mainly with dendritic shafts, are nonsynaptic puncta adhaerentia that are often observed at large
synapses such as the mossy fiber synapses of the hippocampus and calyx of Held synapses in the auditory brain
stem (Sätzler et al. 2002).
Like their presynaptic boutons, the postsynaptic elements
on CA3 pyramidal cell dendrites (the thorny excrescences)
are large and often branched. Branching of spines is a rare
feature of regular spines in the neocortex and hippocampus.
In Fig. 1b, the postsynaptic CA3 pyramidal neuron has been
Golgi-impregnated and gold-toned, allowing the identification of all spines belonging to this identified cell. Regarding
their large dimensions, these complex spines have also been
described as microdendrites. They often contain a spine
apparatus consisting of sacs of endoplasmic reticulum
associated with electron-dense plates. Occasionally, ribosomes are observed at the base of these large spines.
The clear synaptic vesicles of the mossy fiber bouton are
thought to contain the transmitter glutamate (Storm-Mathisen
1981; Terrian et al. 1990). Interestingly, the mossy fibers
also constitutively express both glutamic acid decarboxylase 67 (GAD67) and its product, the inhibitory transmitter
GABA (Sloviter et al. 1996). In addition, the mossy fiber
boutons contain zinc, which allows them to be stained by the
Timm sulphide silver technique for heavy metals (Timm
1958). Dense-core vesicles are often observed, and these
apparently contain neuropeptides such as dynorphin,
enkephalin, cholecystokinin (CCK), and neuropeptide Y
(NPY) (for a review, see Henze et al. 2000). Taken together,
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Fig. 1 Identification of hippocampal mossy fiber synapses by Golgi
impregnation and electron microscopy. a Of the two large mossy fiber
boutons (MF1, MF2), one had been identified in the light microscope
by Golgi impregnation and gold-toning. Gold grains are scattered over
MF1 but still allow the large number of synaptic vesicles to be seen.
The bouton establishes abundant asymmetric synaptic contacts with
CA3 pyramidal cell spines (s) invaginating into the presynaptic
terminal (arrows puncta adhaerentia on a proximal dendritic shaft).
b Golgi impregnation of the postsynaptic pyramidal cell reveals its
large, occasionally branched, complex spines (s) that are postsynaptic
to mossy fiber boutons (MF). Asymmetric synaptic contacts (arrows)
are present on the spines (D parent dendritic shaft). Bars 0.5 μm
the characteristic fine-structural features of mossy fiber
synapses on thorny excrescences of CA3 neurons allow the
unequivocal idenfication of these structures by EM and point
to specialized functions of these contacts when compared
with conventional small cortical synapses (Bischofberger et
al. 2006).
Other targets of mossy fibers and their synaptic
specializations
At the light-microscopic level, the thorny excrescences,
being so intimately associated with mossy fiber expansions,
appeared initially to be the only target structures of granule
cell axons. As mentioned above, these observations seemed
Fig. 2 Large mossy fiber boutons synapse with identified interneuron
dendrites. a Golgi-impregnated and gold-toned dendritic shaft (D) of a
light-microscopically identified basket cell in CA3. A large mossy
fiber bouton (MF) establishes synaptic contacts both with the dendritic
shaft of the identified basket cell (arrow) and with unstained spines (s)
of a pyramidal neuron. b Proximal dendrite (D) of a GABAergic
interneuron in the stratum lucidum of CA3, identified by postembedding immunogold labeling for GABA. A large mossy fiber terminal
(MF) establishes an asymmetric synaptic contact with the GABAimmunolabeled dendrite. Bars 0.5 μm
to exclude synaptic contacts of the mossy fibers with
smooth interneuron dendrites. Conventional EM of the hilar
region and CA3 subsequently confirmed that the large
mossy fiber boutons exclusively contacted thorny excrescences of hilar mossy cells and CA3 pyramidal neurons. To
demonstrate mossy fiber synapses on interneurons, it
became necessary to label these cells and study them
electron-microscopically for contacts with the characteristic
giant terminals of mossy fibers. By using Golgi impregnation and gold toning (Fairén et al. 1977) to label
interneurons in the CA3 region, Frotscher (1985) showed
that giant mossy fiber expansions established asymmetric
synapses with the smooth dendrites of identified interneurons traversing the stratum lucidum. Moreover, these studies
unequivocally showed that a large mossy fiber bouton could
Cell Tissue Res
synapse on a smooth Golgi-impregnated interneuron
dendrite and on unstained thorny excrescences of a nearby
CA3 pyramidal cell (Fig. 2a). These studies with the Golgi
method were later confirmed by immunostaining to identify
interneuron dendrites by their transmitter phenotype
(Frotscher 1989; Fig. 2b).
Whereas these initial studies demonstrated that interneurons were targets of mossy fibers, they relied on the
identification of large mossy fiber boutons by their unique
fine-structural characteristics. This implied that smaller
presynaptic elements of the mossy fibers contacting
interneuron dendrites could have been neglected. Identification of smaller presynaptic elements formed by granule
cell synapses required the complete labeling of the entire
mossy fiber axon with the electron-dense marker biocytin.
Using this approach, Acsády et al. (1998) showed the
existence of two other types of mossy fiber presynaptic
bouton distinct from the giant expansions. They found that
the majority of mossy fiber synapses were formed by small
boutons and filopodial extensions of the giant expansions.
Moreover, these two types of small mossy fiber bouton
showed a clear preference for interneurons, as identified by
double labeling with interneuron-specific markers. Based
on these findings, Acsády and coworkers (1998) concluded
that the majority of mossy fiber synapses formed synaptic
connections with hippocampal interneurons, rather than
Fig. 3 Parvalbumin-positive inhibitory interneurons are targets of
aberrant mossy fiber sprouting after hilar neuron loss induced by
status epilepticus. a1, a2 Low- and high-magnification views of the
dentate gyrus of a kainate-treated rat 22 days after status epilepticus,
showing that early synaptic reorganization in the inner molecular layer
(sm stratum moleculare) targets parvalbumin-positive interneurons
(arrows in a1 recurrent mossy fiber terminals in the inner molecular
layer, arrows in a2 parvalbumin-positive dendrite innervated by
Timm-positive terminals that leave the inner molecular layer, h hilus,
sg granular layer or stratum granulosum). b–f Additional examples of
parvalbumin-positive neurons in the inner molecular layer densely
innervated by Timm-stained terminals of recurrent mossy fibers
(arrows). Bars 25 μm (a1), 12.5 μm (a2–f). Modified from Sloviter
et al. (2006)
Cell Tissue Res
primarily contacting excitatory target cells (mossy cells and
CA3 pyramidal cells). Some interneuron targets of mossy
fibers were identified further by their morphological
characteristics, examples being the various types of
specialized horizontal cells in the stratum lucidum of CA3
(Gulyas et al. 1992; Soriano and Frotscher 1993a; Vida and
Frotscher 2000).
Together, these findings have revealed the wide of
divergence of hippocampal mossy fibers that, in addition
to synapsing with the complex spines of hilar mossy cells
and CA3 pyramidal neurons, contact a variety of interneuron types in both the hilus and the CA3 region (Frotscher et
al. 1994). The excitation of both inhibitory interneurons and
excitatory target cells may provide the inhibition that filters
out weak excitation and favors the transmission of strong
focal excitation to intended target cells (Eccles 1973).
progresses. This observation suggests that the initial hyperexcitability is not caused by mossy fiber sprouting but rather
by the initial loss of neurons (Sloviter 1987). Moreover,
coincident with a fully developed band of supragranular
mossy fibers, there is an increasing hyperinhibition of the
granule cells, as revealed by paired-pulse suppression, and a
resistance to generating epileptiform discharges in response
to afferent excitation (Sloviter et al. 2006). This granule cell
hyperinhibition in chronically epileptic rats is similar to the
hippocampal hyperinhibition observed in human patients
(Cherlow et al. 1977; Colder et al. 1996; Wilson et al. 1998).
As expected, hyperinhibition in epileptic rats is abolished by
application of the GABAA receptor antagonist bicuculline
Mossy fiber sprouting: increase in excitation
or inhibition?
Following mossy cell degeneration, which results in the
denervation of their target cells in the molecular layer,
granule cells “sprout” new axon collaterals and extend them
into the dentate inner molecular layer (Nadler et al. 1980;
Laurberg and Zimmer 1981; Frotscher and Zimmer 1983;
Sloviter et al. 2006). This sprouting is a consistent feature
that follows injury-induced loss of granule cell target
neurons in animal models of epilepsy and in human temporal
lobe epilepsy (TLE; Blümcke et al. 2000). The signals that
trigger mossy fiber sprouting are still unclear, but a role for
brain-derived neurotrophic factor (BDNF) has been suggested (Danzer et al. 2004; Otal et al. 2005). However,
BDNF does not appear to be the only neurotrophic factor
involved in this process, as mossy fiber sprouting has been
found to be similar in slice cultures from wildtype mice and
BDNF knockout animals (Bender et al. 1998). Since the
mossy fibers give rise to excitatory synapses, the lesioninduced aberrant mossy fibers in the inner molecular layer of
the dentate gyrus are generally assumed to increase granule
cell excitability by forming abnormal recurrent excitatory
connections among normally unconnected granule cells
(Tauck and Nadler 1985). This assumption is supported by
early studies on mossy fiber sprouting following denervation; by means of the Golgi/EM technique, granule cell
dendrites had been identified as postsynaptic targets of
sprouting mossy fibers (Frotscher and Zimmer 1983).
However, more recent sequential in vivo recordings from
the same chronically epileptic rats in the awake state have
shown hyperexcitability of the granule cells immediately
after the initial status epilepticus (SE), before mossy fiber
sprouting develops, and a progressive decrease in granule
cell excitability as the mossy fiber sprouting process
Fig. 4 a, b Two boutons of recurrent mossy fibers (MF) in the inner
molecular layer of the dentate gyrus 10 weeks after kainate injection.
The boutons establish asymmetric synaptic contacts (black arrows) on
dendritic shafts (D) of GABAergic interneurons identified by
postembedding immunogold labeling for GABA (white arrow thin
unmyelinated preterminal mossy fiber axon, arrowheads dense-core
vesicles often found in mossy fiber terminals). Bars 0.5 μm. Modified
from Sloviter et al. (2006)
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(Sloviter et al. 2006). These findings, pointing to an
increased GABAA-receptor-mediated inhibition after SE,
suggest a possible causal relationship of the sprouting
process with an increase in inhibition rather than excitation.
To address this hypothesis, Sloviter and colleagues
(2006) have combined Timm staining to label recurrent
mossy fibers and immunostaining for the calcium-binding
protein parvalbumin, which is known to be contained in
major interneuron subtypes. As shown in Fig. 3, many
Timm-positive recurrent mossy fibers densely innervate the
dendrites of inhibitory interneurons. This result strongly
suggests that mossy fibers sprouting to the inner molecular
layer innervate both granule cells and interneurons, a
finding that has been confirmed by GABA-immunogold
labeling and EM. As seen in Fig. 4a,b, giant mossy fiber
terminals establish asymmetric synaptic contacts with
dendritic shafts of GABA-immunopositive neurons. Given
the high degree of divergence of GABAergic interneurons
in the dentate gyrus innervating thousands of granule cells,
the activation of these neurons by convergent recurrent
mossy fiber terminals may cause granule cell hyperinhibition and may thus form the morphological basis of the
paradoxical hyperinhibition recorded in chronic epileptic
rats and humans.
Conclusions
The synapses made by the mossy fibers have been
traditionally described as the second synapse in the
hippocampal trisynaptic excitatory pathway. This excitatory
chain includes synapses of fibers from the entorhinal cortex
with the granule cells (first synapse), which in turn activate
CA3 pyramidal neurons via mossy fiber synapses (second
synapse). The third synapse is formed by contacts of the
Schaffer collaterals on CA1 pyramidal cells (Andersen et al.
1971). Work over the last 30 years has established that this
view of hippocampal organization as a serial trisynaptic
circuit is an oversimplification. In particular, the synapses
formed by mossy fibers have turned out to be more
complex than anticipated. With their synapses via small
boutons, filopodial extensions, and the contacts of large
boutons with dendritic shafts of GABAergic neurons,
mossy fiber-interneuron synapses outnumber the synapses
with CA3 pyramidal cells by approximately an order of
magnitude (Acsády et al. 1998). The resulting net effect on
the CA3 region may be inhibition, with only a few CA3
pyramidal cells being activated in a highly selective manner
(for a review of functional properties of mossy fiber
synapses, see Bischofberger et al. 2006). Under pathologic
conditions such as chronic epilepsy, the observed mossy
fiber synapses with GABAergic interneurons may underlie
the granule cell hyperinhibition recorded from chronic
epileptic animals (Sloviter et al. 2006). Activation of
GABAergic dentate interneurons via sprouting mossy fibers
may efficiently counteract granule cell excitation; this is
likely because GABAergic basket cells, axo-axonic cells,
and interneurons innervating granule cell dendrites are
known for their abundant contacts with numerous granule
cells (Halasy and Somogyi 1993; Soriano and Frotscher
1989, 1993b). Further complicating the story is the
observation that granule cells can express GAD67 and
GABA, and that the concentrations of GAD and GABA are
increased seven-fold by increased activity (Sloviter et al.
1996; Sloviter 2003). Therefore, granule cells may produce
inhibition indirectly, via the activation of inhibitory
neurons, and directly, via the release of GABA, at least
under pathophysiologic conditions (for a review, see
Gutierrez 2005). The excitatory mossy fiber synapse is
thus beginning to disclose its seemingly paradoxical role
as an important component of hippocampal inhibitory
circuits.
References
Acsády L, Kamondi A, Sík A, Freund T, Buzsáki G (1998)
GABAergic cells are the major postsynaptic targets of mossy
fibers in the rat hippocampus. J Neurosci 18:3386–3403
Amaral DG (1978) A Golgi study of cell types in the hilar region of
the hippocampus in the rat. J Comp Neurol 182:851–914
Andersen P, Bliss TVP, Skrede KK (1971) Lamellar organization of
hippocampal excitatory pathways. Exp Brain Res 13:222–238
Bender R, Heimrich B, Meyer M, Frotscher M (1998) Hippocampal
mossy fiber sprouting is not impaired in brain-derived neurotrophic factor-deficient mice. Exp Brain Res 120:399–402
Bischofberger J, Engel D, Frotscher M, Jonas P (2006) Mechanisms
underlying the efficacy of transmitter release at mossy fiber
synapses in the hippocampal network. Pflügers Arch (in press)
Blackstad TW (1956) Commissural connections of the hippocampal
region of the rat, with special reference to their mode of
termination. J Comp Neurol 105:417–537
Blackstad TW (1958) On the termination of some afferents to the
hippocampus and fascia dentata: an experimental study in the rat.
Acta Anat (Basel) 35:202–214
Blackstad TW, Kjaerheim A (1961) Special axodendritic synapses in
the hippocampal cortex: electron and light microscopic studies on
the layer of mossy fibers. J Comp Neurol 117:113–159
Blümcke I, Suter B, Behle K, Kuhn R, Schramm J, Elger CE, Wiestler
OD (2000) Loss of hilar mossy cells in Ammon’s horn sclerosis.
Epilepsia 41 (Suppl 6):S174–S180
Cherlow DG, Dymond AM, Crandall PH, Walter RD, Serafetinides
EA (1977) Evoked response and after-discharge thresholds to
electrical stimulation in temporal lobe epileptics. Arch Neurol
34:527–531
Chicurel ME, Harris KM (1992) Three-dimensional analysis of the
structure and composition of CA3 branched dendritic spines and
their synaptic relationships with mossy fiber boutons in the
hippocampus. J Comp Neurol 325:169–182
Colder BW, Wilson CL, Frysinger RC, Chao LC, Harper RM, Engel J
Jr (1996) Neuronal synchrony in relation to burst discharge in
epileptic human temporal lobes. J Neurophysiol 75:2496–2508
Cell Tissue Res
Danzer SC, He X, McNamara JO (2004) Ontogeny of seizure-induced
increases in BDNF immunoreactivity and TrkB receptor activation
in rat hippocampus. Hippocampus 14:345–355
Deller T, Leranth C (1990) Synaptic connections of neuropeptide Y
(NPY) immunoreactive neurons in the hilar area of the rat
hippocampus. J Comp Neurol 300:433–447
Eccles JC (1973) The understanding of the brain. McGraw-Hill, New
York
Fairén A, Peters A, Saldanha J (1977) A new procedure for examining
Golgi impregnated neurons by light and electron microscopy.
J Neurocytol 6:311–337
Förster E, Zhao S, Frotscher M (2006) Laminating the hippocampus.
Nat Rev Neurosci 7:259–267
Frotscher M (1985) Mossy fibres form synapses with identified
pyramidal basket cells in the CA3 region of the guinea pig
hippocampus: a combined Golgi-electron microscope study.
J Neurocytol 14:245–259
Frotscher M (1989) Mossy fiber synapses on glutamate decarboxylaseimmunoreactive neurons: evidence for feed-forward inhibition
in the CA3 region of the hippocampus. Exp Brain Res 75:
441–445
Frotscher M, Zimmer J (1983) Lesion-induced mossy fibers to the
molecular layer of the rat fascia dentata: identification of
postsynaptic granule cells by the Golgi/EM technique. J Comp
Neurol 215:299–311
Frotscher M, Soriano E, Misgeld U (1994) Divergence of hippocampal
mossy fibers. Synapse 16:148–160
Golgi C (1886) Sulla fina anatomica degli organi centrali del sistema
nervoso. Hoepli, Milan
Gulyas AI, Miettinen R, Jacobowitz DM, Freund TF (1992) Calretinin
is present in non-pyramidal cells of the rat hippocampus. I. A
new type of neuron specifically associated with the mossy fibre
system. Neuroscience 48:1–27
Gutierrez R (2005) The dual glutamatergic-GABAergic phenotype of
hippocampal granule cells. Trends Neurosci 28:297–303
Halasy K, Somogyi P (1993) Subdivisions in the multiple GABAergic
innervation of granule cells in the dentate gyrus of the rat
hippocampus. Eur J Neurosci 5:411–429
Hamlyn LH (1962) The fine structure of the mossy fibre endings in
the hippocampus of the rabbit. J Anat 97:112–120
Henze DA, Urban NN, Barrionuevo G (2000) The multifarious
hippocampal mossy fiber pathway: a review. Neuroscience
98:407–427
Koelliker A (1896) Handbuch der Gewebelehre des Menschen.
Zweiter Band: Nervensystem des Menschen und der Thiere.
Wilhelm Engelmann, Leipzig
Laurberg S, Zimmer J (1981) Lesion-induced sprouting of hippocampal
mossy fiber collaterals to the fascia dentata in developing and adult
rats. J Comp Neurol 200:433–459
Leranth C, Frotscher M (1986) Synaptic connections of cholecystokininimmunoreactive neurons and terminals in the rat fascia dentata:
a combined light and electron microscopic study. J Comp Neurol
254:51–64
Lorente de Nó R (1934) Studies on the structure of the cerebral cortex.
II. Continuation of the study of the ammonic system. J Psychol
Neurol 46:113–177
Nadler JV, Perry BW, Cotman CW (1978) Intraventricular kainic acid
preferentially destroys hippocampal pyramidal cells. Nature
271:676–677
Nadler JV, Perry BW, Cotman CW (1980) Selective reinnervation of
hippocampal area CA1 and the fascia dentata after destruction of
CA3–CA4 afferents with kainic acid. Brain Res 182:1–9
Otal R, Martinez A, Soriano E (2005) Lack of TrkB and TrkC
signaling alters the synaptogenesis and maturation of mossy fiber
terminals in the hippocampus. Cell Tissue Res 319:349–358
Ramón y Cajal SR (1911) Histologie du Système Nerveux de
l’Homme et des Vertébrés, vol. II. Maloine, Paris
Sätzler K, Söhl LF, Bollmann JH, Borst JGB, Frotscher M, Sakmann
B, Lübke JHR (2002) Three-dimensional reconstruction of a
calyx of Held and its postsynaptic principal neuron in the medial
nucleus of the trapezoid body. J Neurosci 22:10567–10579
Schmidt-Hieber C, Jonas P, Bischofberger J (2004) Enhanced synaptic
plasticity in newly generated granule cells of the adult hippocampus.
Nature 429:184–187
Seress L, Frotscher M (1990) Morphological variability is a
characteristic feature of granule cells in the primate fascia
dentate: a combined Golgi/electron microscope study. J Comp
Neurol 293:253–267
Sloviter RS (1987) Decreased hippocampal inhibition and a selective
loss of interneurons in experimental epilepsy. Science 235:73–76
Sloviter RS (2003) Excitatory dentate granule cells normally contain
GAD and GABA, but does that make them GABAergic, and do
seizures shift granule cell function in the inhibitory direction?
Epilepsy Curr 3:3–5
Sloviter RS, Valiquette G, Abrams GM, Ronk EC, Sollas AL, Paul LA,
Neubort S (1989) Selective loss of hippocampal granule cells in
the mature rat brain after adrenalectomy. Science 243:535–538
Sloviter RS, Dichter MA, Rachinsky TL, Dean E, Goodman JH,
Sollas AL, Martin DL (1996) Basal expression and induction of
glutamate decarboxylase and GABA in excitatory granule cells
of the rat and monkey hippocampal dentate gyrus. J Comp
Neurol 373:593–618
Sloviter RS, Zappone CA, Harvey BD, Frotscher M (2006) Kainic
acid-induced recurrent mossy fiber innervation of dentate gyrus
inhibitory interneurons: possible anatomical substrate of granule
cell hyperinhibition in chronically epileptic rats. J Comp Neurol
494:944–960
Soriano E, Frotscher M (1989) A GABAergic axo-axonic cell in the
fascia dentata controls the main excitatory hippocampal pathway.
Brain Res 503:170–174
Soriano E, Frotscher M (1993a) Spiny nonpyramidal neurons in the
CA3 region of the rat hippocampus are glutamate-like immunoreactive and receive convergent mossy fiber input. J Comp
Neurol 332:435–448
Soriano E, Frotscher M (1993b) GABAergic innervation of the rat
fascia dentata: a novel type of interneuron in the granule cell
layer with extensive axonal arborization in the molecular layer.
J Comp Neurol 334:385–396
Storm-Mathisen J (1981) Glutamate in hippocampal pathways. Adv
Biochem Psychopharmacol 27:43–55
Tauck DL, Nadler JV (1985) Evidence of functional mossy fiber
sprouting in hippocampal formation of kainic acid-treated rats.
J Neurosci 5:1016–1022
Terrian DM, Gannon RL, Rea MA (1990) Glutamate is the
endogenous amino acid selectively released by rat hippocampal
mossy fiber synaptosomes concomitantly with prodynorphinderived peptides. Neurochem Res 15:1–5
Timm F (1958) Zur Histochemie der Schwermetalle, das SulfidSilber-Verfahren. Dtsch Z Gesamte Gerichtl Med 46:706–711
Vida I, Frotscher M (2000) A hippocampal interneuron associated with
the mossy fiber system. Proc Natl Acad Sci USA 97:1275–1280
Wilson CL, Khan SU, Engel J Jr, Isokawa M, Babb TL, Behnke EJ
(1998) Paired pulse suppression and facilitation in human
epileptogenic hippocampal formation. Epilepsy Res 31:211–230