Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network

Abstract

It is widely accepted that the hippocampus plays a major role in learning and memory. The mossy fiber synapse between granule cells in the dentate gyrus and pyramidal neurons in the CA3 region is a key component of the hippocampal trisynaptic circuit. Recent work, partially based on direct presynaptic patch-clamp recordings from hippocampal mossy fiber boutons, sheds light on the mechanisms of synaptic transmission and plasticity at mossy fiber synapses. A high Na + channel density in mossy fiber boutons leads to a large amplitude of the presynaptic action potential. Together with the fast gating of presynaptic Ca 2+ channels, this generates a large and brief presynaptic Ca 2+ influx, which can trigger transmitter release with high efficiency and temporal precision. The large number of release sites, the large size of the releasable pool of vesicles, and the huge extent of presynaptic plasticity confer unique strength to this synapse, suggesting a large impact onto the CA3 pyramidal cell network under specific behavioral conditions. The characteristic properties of the hippocampal mossy fiber synapse may be important for pattern separation and information storage in the dentate gyrus-CA3 cell network.Keywords Presynaptic recording . Mossy fiber boutons . Mossy fiber synapses . Hippocampus . Autoassociative networks . Episodic memory . Synaptic efficacyThe mossy fiber synapse: a key connection in the hippocampal networkThe hippocampal formation consists of three types of principal neurons: granule cells in the dentate gyrus, CA3 pyramidal cells, and CA1 pyramidal neurons. These cells are interconnected by glutamatergic synapses, forming the classical trisynaptic circuit (Fig. 1a,b). Dentate gyrus granule cells receive excitatory glutamatergic input from layer 2 pyramidal cells of the entorhinal cortex and project to CA3 pyramidal cells. CA3 pyramidal cells project to CA1 cells, which in turn project to the subiculum and back to the entorhinal cortex [4]. In addition to this trisynaptic circuit, there is also a direct input from the entorhinal cortex to both CA3 and CA1 pyramidal cells. Furthermore, CA3 pyramidal neurons are extensively connected to each other via recurrent collateral synapses.The nonmyelinated axons of the granule cells, the socalled mossy fibers, show several structural properties that distinguish them from the other synaptic pathways [39]. They project to the CA3 region, mainly traveling within a narrow band termed "stratum lucidum." Several (∼15) large "giant" boutons (∼3-5-μm diameter) emerge from a single mossy fiber axon, either arranged in an en passant manner or attached to the main axon via a short perpendicular axonal branch [1,8,29,31] (Fig. 1c,d). A large mossy fiber bouton typically contacts only a single CA3 pyramidal neuron [21], and a mossy fiber axon contacts a given CA3 pyramidal neuron only once, as boutons are ∼150 μm apart. As the rat hippocampus contains ∼1 million granule cells

Differential Gating and Recruitment of P/Q-, N-, and R-Type Ca2+Channels in Hippocampal Mossy Fiber Boutons

“…channels by presynaptic voltage waveforms Several recent studies suggest that signaling in mossy fiber axons and MFBs is highly complex (for review, see Bischofberger et al, 2006a) (see also Debanne, 2004). First, the duration of the presynaptic action potential is not constant, but shows broadening during repetitive stimulation (Geiger and Jonas, 2000).…”

“…The mossy fiber-CA3 pyramidal neuron synapse is a key synapse in the trisynaptic circuitry of the hippocampus (Brown and Johnston, 1983;Henze et al, 2002;Nicoll and Schmitz, 2005;Bischofberger et al, 2006a). Although this synapse is widely used as a model to study presynaptic plasticity (Salin et al, 1996;Toth et al, 2000), the basic mechanisms of presynaptic Ca 2ϩ signaling are incompletely understood.…”

Functional Specificity of Mossy Fiber Innervation of GABAergic Cells in the Hippocampus

“…Second, our data indicate that GABAergic mechanisms that may shape the highly efficient activation of CA3 pyramidal cells on short bursts of repetitive granule cell discharges ("conditional detonator") (Henze et al, 2002; see also Lawrence and McBain, 2003) may involve cell type-specific, differential engagement of perisomatic and dendritic GABAergic synapses within CA3, as well as the GABAergic modulation of extrahippocampal areas. Future research will be needed to clarify how the target cellspecific excitation of CA3 GABAergic neurons by MFs contribute to the storage and recall of information and pattern separation during normal behaviors (Nakazawa et al, 2002;Bischofberger et al, 2006a;Leutgeb et al, 2007;Nakashiba et al, 2008), and to the special vulnerability of certain CA3 GABAergic cells (especially SLCs) after excitotoxic insults (Arabadzisz and Freund, 1999).…”

Chapter 13 Differential mechanisms of transmission and plasticity at mossy fiber synapses

“…This might suggest that the mechanism underlying transmitter release at each terminal is controlled by different synaptic machinery. At the large mossy fiber bouton, transmitter exocytosis is controlled by the high threshold P/Q (Cav2.1) and N-type (Cav2.2) voltage-gated calcium channels (VGCCs), with some evidence for a minor role for R-type VGCCs (Bischofberger et al, 2006; Nicoll and Schmitz, 2006). We considered it possible that the filopodial extensions may utilize a different compliment of VGCCs to trigger transmitter release.…”

“…The purpose of the present review is to highlight several aspects of this synapse as they pertain to a novel mechanism of bidirectional control of synaptic plasticity at mossy fiber synapses made onto hippocampal stratum lucidum interneurons. It is not my intention to pour over all that is known regarding the mossy fiber synapse since many have explored this topic exhaustively in the past and interested readers are directed to other fine reviews (Henze et al, 2000;Urban et al, 2001;Lawrence et al, 2003;Bischofberger et al, 2006;Nicoll and Schmitz, 2005). …”