Elsevier

Progress in Brain Research

Volume 163, 2007, Pages 109-132, 804-805
Progress in Brain Research

Mossy fiber synaptic transmission: communication from the dentate gyrus to area CA3

https://doi.org/10.1016/S0079-6123(07)63006-4Get rights and content

Abstract

Communication between the dentate gyrus (DG) and area CA3 of the hippocampus proper is transmitted via axons of granule cells — the mossy fiber (MF) pathway. In this review we discuss and compare the properties of transmitter release from the MFs onto pyramidal neurons and interneurons. An examination of the anatomical connectivity from DG to CA3 reveals a surprising interplay between excitation and inhibition for this circuit. In this respect it is particularly relevant that the major targets of the MFs are interneurons and that the consequence of MF input into CA3 may be inhibitory or excitatory, conditionally dependent on the frequency of input and modulatory regulation. This is further complicated by the properties of transmitter release from the MFs where a large number of co-localized transmitters, including GABAergic inhibitory transmitter release, and the effects of presynaptic modulation finely tune transmitter release. A picture emerges that extends beyond the hypothesis that the MFs are simply “detonators” of CA3 pyramidal neurons; the properties of synaptic information flow from the DG have more subtle and complex influences on the CA3 network.

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

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    Both authors contributed equally to this work.

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