Mossy fiber synaptic transmission: communication from the dentate gyrus to area CA3☆
Section snippets
MF anatomy: does form follow function?
The MFs form three types of synaptic contacts onto its target neurons. First, and most notably, are the large expansions that synapse onto CA3 pyramidal neurons. The large boutons appear at approximately 150 μm intervals (Blackstad et al., 1970) and a single granule cell contacts approximately 15 pyramidal neurons (each terminal synapses onto a single pyramidal neuron). One CA3 pyramidal neuron may receive up to a total of approximately 50 MF inputs only (Claiborne et al., 1986; Amaral et al.,
Excitatory–inhibitory conductance sequence
Yamamoto (1972) was the first to utilize brain slice methods and intracellular recording to study MF synaptic transmission onto CA3 pyramidal neurons. Stimulation of the granule cell layer triggered a biphasic response composed of a small compound excitatory postsynaptic potential (EPSP) followed by a larger, overlapping compound inhibitory postsynaptic potential (IPSP), presumably mediated either by feed-forward/feed-back inhibition or the direct stimulation of inhibitory interneurons (
Properties of transmitter release from MF synapses
Granule cells discharge action potentials down the MFs at basal rates less than 0.5 Hz (Jung and McNaughton, 1993), though firing rates may reach up to 50 Hz during certain types of behaviors (Skaggs et al., 1996; Wiebe and Staubli, 1999; Henze et al., 2002b) and conduction velocity is approximately 7 m/s, consistent with the MFs being an unmyelinated pathway (Langdon et al., 1993). Upon reaching synaptic terminals, presynaptic action potentials trigger synaptic transmission by eliciting Ca2+
Quantal nature of transmission at the MF-CA3 pyramidal neuron synapse
The strong frequency-dependent facilitation of MF synaptic transmission onto CA3 pyramidal neurons implies that the initial probability of transmitter release is small. If the probability of release were high, either a ceiling effect would limit an increase in release (assuming that there is a large reserve pool of primed vesicles) or, alternatively, one could observe synaptic depression due to the refractory period produced by a lack of primed vesicles. Indeed, quantal analysis of unitary
Evidence for multiple neurotransmitters/modulators in the granule cells
Glutamate is believed to be the primary excitatory neurotransmitter released from the MFs (Crawford and Connor, 1973; Terrian et al., 1988), and MF EPSPs are blocked by glutamate receptor antagonists (Sawada et al., 1983). The neuronal glutamate transporter (EAAC1) is the most abundant uptake mechanism and is selectively enriched in hippocampal principal neurons, including DG granule cells (Rothstein et al., 1994). The presynaptic and postsynaptic actions of glutamate released from the MFs are
Presynaptic modulation
As mentioned above, a number of neuromodulators control transmitter release from the MFs. Glutamate and GABA are also important presynaptic modulators of MF synaptic transmission transmission. In particular, one of the unique properties of MF synaptic transmission, in contrast to transmitter release from recurrent synapses onto CA3 pyramidal neurons, is its sensitivity to metabotropic glutamate receptor (mGluR) agonists; mGluR agonists depress MF synaptic transmission (Manzoni et al., 1995;
Co-localization of plasma membrane transporters of glutamate and GABA
Glutamate transport is the major mechanism controlling extracellular glutamate levels, preventing excitotoxicity, and averting neural damage associated with hyperexcitability. As mentioned above, the neuronal glutamate transporter (EAAC1) is expressed in granule cells and, surprisingly, in a number of GABAergic neurons (Rothstein et al., 1994; He et al., 2002; Sepkuty et al., 2002). Therefore, it has been suggested that besides controlling extracellular glutamate levels, its function is linked
Co-localization of the vesicular transporters for glutamate (VGlut-1) and GABA (VGAT)
Because glutamate is a general metabolic substrate and serves as the precursor of inhibitory transmitter GABA, glutamate immunoreactivity is not specific to glutamatergic neurons. Therefore, the detection of glutamate vesicular transporter(s) has been used to establish the glutamatergic phenotype of neurons. As expected for glutamatergic neurons, the MF terminals of the granule cells contain the glutamate vesicular transporter VGlut-1 (Bellocchio et al., 1998; Kaneko et al., 2002). In
Postsynaptic responses of CA3 pyramidal neurons to MF glutamatergic input
As mentioned above, glutamate is believed to be the primary excitatory neurotransmitter released from the MFs (Crawford and Connor, 1973; Terrian et al., 1988). The primary ionotropic glutamate receptors mediating the fast synaptic response at the MF synapse are a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptors (Lanthorn et al., 1984; Neuman et al., 1988; Ito and Sugiyama, 1991; Jonas et al., 1993). Voltage-clamp analysis of unitary and compound excitatory postsynaptic
Are MF synapses onto CA3 pyramidal neurons detonators?
It is not surprising that LFS of the MFs fails to routinely trigger spikes, given many of the points made above. For example, the major target of the MFs in area CA3 involves the activation of feed-forward inhibitory circuits. Glutamate is co-released with GABA, and a wide-array of other neuromodulators, which potentially inhibit MF transmission. CA3 pyramidal cells also have a threshold that is 10–15 mV from resting potential (Podlogar and Dietrich, 2006). There is a large amplitude unitary
The granule cells simultaneously release glutamate and GABA: electrophysiological evidence
Indirect but compelling evidence has accumulated over the last years of the co-release of glutamate and GABA from the MFs. The first electrophysiological evidence of GABAergic transmission from the MFs to CA3 agreed with the immunohistochemical observations showing that seizures transiently upregulated the expression of GAD65 and GAD67 (Schwarzer and Sperk, 1995; Sloviter et al., 1996). Indeed, it was shown that stimulation of the MFs produced monosynaptic GABA-mediated transmission in
Long-term plasticity at the MF CA3 synapse
Like other excitatory synapses in the hippocampal formation, the MF synapse expresses LTP in response to a brief episode of HFS (Yamamoto et al., 1980). As described above, the MF terminal field contains a lower density of NMDA receptors compared with other areas of the hippocampus. This observation motivated Harris and Cotman (1986) to test whether LTP at the MF synapse was dependent on NMDA receptors. They found that in the presence of NMDA receptor antagonists, HFS of the MFs was still
CA3-interneuron synapses
As discussed above, the majority of MF synaptic contacts are onto GABAergic interneurons (Acsady et al., 1998) of which there are a wide variety of subtypes, typically characterized based on a combination of parameters including cell body location, axonal projection, morphology, co-localized peptides, and calcium binding protein content (Parra et al., 1998). Of particular interest are a class of bipolar interneurons whose dendrites primarily reside along and within s. lucidum (Spruston et al.,
Communication from DG to CA3: exciting yet inhibiting
A picture is emerging that relates the contribution of MF transmission to excitation and inhibition in area CA3, both in terms of the repertoire of neurotransmitters/modulators released from the fibers but also with respect to circuitry that is required to take into account inhibitory neurons. At low frequencies (<0.5 Hz), frequency facilitation of the MF-CA3 pyramidal neuron synapse is weak and the probability of eliciting a spike is low (Henze et al., 2002b). Furthermore, in this frequency
References (262)
- et al.
Neurotrophin trafficking by anterograde transport
Trends Neurosci.
(1998) - et al.
Neurons, numbers and the hippocampal network
Prog. Brain Res.
(1990) - et al.
Modulation of transmitter release by presynaptic resting potential and background calcium levels
Neuron
(2005) Feed-forward inhibition in the hippocampal formation
Prog. Neurobiol.
(1984)- et al.
The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation
Neuron
(1994) - et al.
Commissural synapses, but not mossy fiber synapses, in hippocampal field CA3 exhibit associative long-term potentiation and depression
Brain Res.
(1989) Dynorphins are endogenous opioid peptides released from granule cells to act neurohumorly and inhibit excitatory neurotransmission in the hippocampus
Prog. Brain Res.
(2000)- et al.
Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus
Neuron
(2001) - et al.
Changes in extracellular glutamate and GABA levels in the hippocampal CA3 and CA1 areas and the induction of glutamic acid decarboxylase-67 in dentate granule cells of rats treated with kainic acid
Brain Res.
(1998) - et al.
Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+
Neuron
(1990)
Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures
Neuroscience
Presynaptic action potential amplification by voltage-gated Na+ channels in hippocampal mossy fiber boutons
Neuron
Presence of gamma-aminobutyric acid transporter mRNA in interneurons and principal cells of rat hippocampus
Neurosci. Lett.
The distribution of cholecystokinin-like immunoreactivity in the hippocampal formation of the guinea pig: localization in the mossy fibers
Brain Res.
Seizures, neuropeptide regulation, and mRNA expression in the hippocampus
Prog. Brain Res.
Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons
Neuron
Electrophysiological Studies of Hippocampal Neurons. I. Configuration and laminar analysis of the “resting” potential gradient, of the main-transient response to perforant path, fimbrial and mossy fiber volleys and of “spontaneous” activity
Electroencephalogr. Clin. Neurophysiol.
The expression of GABA in mossy fiber synaptosomes coincides with the seizure-induced expression of GABAergic transmission in the mossy fiber synapse
Exp. Neurol.
The GABAergic phenotype of the “glutamatergic” granule cells of the DG
Prog. Neurobiol.
The dual glutamatergic-GABAergic phenotype of hippocampal granule cells
Trends Neurosci.
Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl d-aspartate antagonists
Neurosci. Lett.
BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF
Neuron
Uptake and metabolism of gamma-aminobutyric acid by neurones and glial cells
Biochem. Pharmacol.
Characterization of neuropeptide Y receptor subtypes in the normal human brain, including the hypothalamus
Neuroscience
Loss of dynorphin-mediated inhibition of voltage-dependent Ca2+ currents in hippocampal granule cells isolated from epilepsy patients is associated with mossy fiber sprouting
Neuroscience
Mu opioids enhance mossy fiber synaptic transmission indirectly by reducing GABAB receptor activation
Brain Res.
Synthetic omega-conotoxin blocks synaptic transmission in the hippocampus in vitro
Neurosci. Lett.
GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus
J. Neurosci.
Combined analog and action potential coding in hippocampal mossy fibers
Science
Synaptic extensions from the mossy fibers of the fascia dentata
Anat. Embryol. (Berl.)
Development of the mossy fibers of the DG: I. A light and electron microscopic study of the mossy fibers and their expansions
J. Comp. Neurol.
Activation of presynaptic P2×7-like receptors depresses mossy fiber-CA3 synaptic transmission through p38 mitogen-activated protein kinase
J. Neurosci.
B-ephrin reverse signaling is required for NMDA-independent long-term potentiation of mossy fibers in the hippocampus
J. Neurosci.
Temporal sequence compression by an integrate-and-fire model of hippocampal area CA3
J. Comput. Neurosci.
Conductance mechanism responsible for long-term potentiation in monosynaptic and isolated excitatory synaptic inputs to hippocampus
J. Neurophysiol.
The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission
J. Neurosci.
GABA and GABAA receptors at hippocampal mossy fibre synapses
Eur. J. Neurosci.
BDNF and NT-3 induce intracellular Ca++ elevation in hippocampal neurones
Neuroreport
Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network
Pflugers Arch.
Distribution of hippocampal mossy fibers in the rat. An experimental study with silver impregnation methods
J. Comp. Neurol.
Special axo-dendritic synapses in the hippocampal cortex: electron and light microscopic studies on the layer of mossy fibers
J. Comp. Neurol.
Characterization of nerve growth factor (NGF) release from hippocampal neurons: evidence for a constitutive and an unconventional sodium-dependent regulated pathway
Eur. J. Neurosci.
Substance P innervation of the rat hippocampal formation
J. Comp. Neurol.
Kainate receptors and the induction of mossy fibre long-term potentiation
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Adenosine-containing neurons in the brain localized by immunocytochemistry
J. Neurosci.
Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies
J. Neurosci.
Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat
J. Neurosci.
Dentate EEG spikes and associated interneuronal population bursts in the hippocampal hilar region of the rat
J. Neurophysiol.
Assessing the role of GLUK5 and GLUK6 at hippocampal mossy fiber synapses
J. Neurosci.
Voltage-clamp analysis of mossy fiber synaptic input to hippocampal neurons
J. Neurophysiol.
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Both authors contributed equally to this work.