PART I Investigations on Learning-Induced Remodeling of Hippocampal Mossy Fibers: The Role of Presynaptic Structural Plasticity in Long-Term Memory Chapter Introduction 1.1 Introduction of hippocampal mossy fibers 1.1.1 Anatomy of the hippocampal mossy fibers 1.1.1.1 Introduction of the hippocampus The hippocampus, a major component of the brain, has been considered to play an important role in the formation of new memories and in the consolidations of information from shortterm memory to long-term memory Anatomically, the hippocampus proper has three subdivisions: CA3, CA2, and CA1 (CA: cornu ammonis) Together with other regions, including the dentate gyrus, subiculum, presubiculum, parasubiculum, and entorhinal cortex, constitute the hippocampal formation Figure 1.1 (Neves et al., 2008) shows the schematic diagram of the circuit in the hippocampal formation The entorhinal cortex is the first step to receive much of the neocortical input in the intrinsic hippocampal circuit Neurons in the superficial layers (layer II) of the entorhinal cortex give rise to axons that are projecting to the dentate gyrus The projections from the entorhinal cortex to the dentate gyrus, conveying the polymodal sensory information, make up one of the major hippocampal input pathways called the perforant path Perforant path axons form excitatory synaptic contacts to the dendrites of granule cells in dentate gyrus: axons from the medial and lateral entorhinal cortices innervate the middle and outer molecular layers of dentate gyrus, respectively Similarly, the granule cells of the dentate gyrus, project to the dendrites of the pyramidal cells in the CA3 through their axons which are called mossy fibers (MFs) In turn, the pyramidal cells of CA3 are the source of the major input to the CA1, comprising of the Schaffer collaterals These three sequential projections, traditionally called trisynaptic circuits, are the major pathways in the hippocampus In addition to this trisynaptic circuit, there are also other networks interconnecting two subfields For example, the distal apical dendrites of CA1 pyramidal neurons receive a direct input from layer III cells of the entorhinal cortex CA1, inversely, projects across subiculum to the inner deep layer of the entorhinal cortex Through these connections, CA1 and the subiculum enclose the hippocampal processing loop that begins in the superficial layers of the entorhinal cortex and ends in its deep layers Furthermore, there is also a direct input from the entorhinal cortex to CA3 pyramidal cells CA3 pyramidal neurons are extensively connected to each other via recurrent collateral synapses: associational/commissural synapse (Amaral & Lavenex, The Hippocampus Book, 2007) Figure 1.1 Basic anatomy of the hippocampus formation (Neves et al., 2008) Transverse view of the hippocampus in the middle shows the trisynaptic loop interconnecting the hippocampal subfields, indicating the critical role of the hippocampus in the information processing 1.1.1.2 Introduction of the mossy fibers As mentioned in 1.1.1.1, the hippocampal MFs are the axons which arise from the granule cells of the dentate gyrus The MFs pathway, the only efferent projections from dentate gyrus to neurons in the hilus and CA3 area, comprise the second synapse of the hippocampal circuit In this trisynaptic model of the hippocampus, based on the observations of the MFs presynapses and their locations, the basic functional role of MFs it is clear that the MFs pathway provides a strong excitatory input to the proximal apical dendrites of CA3 pyramidal cells (Blackstad and Kjaerheim, 1961; Andersen et al., 1966; Andersen et al., 1971) The MFs form distinct synapses with excitatory and inhibitory cells of the hilus and area CA3 It has been shown that the MFs form synapses on large thorny excrescences of CA3 pyramidal neurons (Amaral and Dent, 1981) Besides, the MFs also make synaptic connecting to the MF-associated inhibitory interneurons (Maccaferri et al., 1988; Vida and Frotscher, 2000) In the rodents, each of the granule cells in the dentate gyrus gives rise to a single MF axon and the main MF axon gives rise to a great amount of fine collaterals to provide input to the polymorphic neurons of the hilus (Henze et al., 2000) Furthermore, the main MF axons leave the hilus and pass through CA3 area in a narrow band which is called the stratum lucidum (SL), corresponding approximately to the proximal 100 μm of the apical dendrites of CA3 pyramidal cells (Henze et al., 2000) Besides, there are present large numbers of active zones and their associated post-synaptic densities in the MFs synaptic complex (Acsady et al., 1998; Chicurel and Harris 1992) Therefore, because of its unique and basic structural property, the hippocampal MFs pathway is usually considered one of the pre-synaptic models in the investigations on the presynaptic morphological axonal readjustments 1.1.2 Histology of Mossy fiber pathways It has been studied that the MFs terminals contain the highest concentration of zinc in the brain by Frederickson in 1983 This heavy metal is found in large dense core vesicles and is released from the MFs Timm’s staining method for heavy metals has the ability to reveal zinc, therefore it can be considered as an efficient histological tool to identify the distribution of the MFs using the light microscope (Figure 1.2, reference image from Rekart et al., 2007a) Figure 1.2 illustrates the organization of the MFs terminal regions in CA3 In CA3c, the proximal portion of CA3 that is close to the dentate gyrus, the MFs are distributed below, within, and above the pyramidal cell layer The fibers located below the layer are generally called the infrapyramidal MFs (INFRA; white arrow in Figure 1.2), while, the fibers located within the pyramidal cell layer are called the intrapyramidal MFs (INTRA; white arrowhead in Figure 1.2) Often these two are treated as one pathway, the infra- and intrapyramidal MF (IIPMF) pathway The IIPMF pathway originates from hippocampal granule cells and terminates primarily upon the basal dendrites of superficial pyramidal cells in CA3b and CA3c Figure 1.2 Hippocampal MFs pathways of a Wistar rat, distinguished by the Timm’s stain and cresyl violet counterstain Image is from reference Rekart et al., 2007a The fibers located above the pyramidal cell layer are called the suprapyramidal MFs, which terminate in a relatively narrow zone (SL in Figure 1.2) located within the proximal apical dendrites of CA3 pyramidal cell in CA3a Granule cell MFs projections also terminate infrapyramidally in the stratum oriens (SO) and intrapyramidally in the stratum pyramidale (SP) in CA3a In addition to the pathways above in a lamellar organization, there are descending MFs along the longitudinal axis of the hippocampus The descending pathway travels from the granule cell layer transversely through the SL, synapses on more temporally located CA3 cells (Lorente, 1934; Swanson et al., 1978; Amaral et al., 1981) The maximum distance of the descending MFs reaches as far as mm in the temporal direction (Amaral and Witter, 1989) The MF axons form three different types of synaptic contacts with the targets in the hilus and CA3 (Henze et al., 2000) Firstly, the characteristic large boutons, which are up to 4-10 µm in diameter, synapse with the hilar mossy cells and proximal dendrites of CA3 pyramidal cells These boutons appear as a cluster of large vesicles that containing zinc as one of the neurotransmitters in the MFs Their large size has attracted the attention of physiologists interested in using them for patch-clamp studies on transmitter release (Henze et al., 2000) Besides, the giant boutons together with the associated postsynaptic densities demonstrate the presence of multiple active synaptic zones In this way, the CA3 pyramidal cells are associated with a number of the active zones associated with the MFs pathway Therefore, the MFs pathway is believed to have the potential to provide a strong excitatory input and trigger the action potential generation in CA3 pyramidal cells The remaining two types of MFs synaptic contacts are small filopodial extensions emanated from the large MFs boutons They are associated with the GABA (γaminobutyric acid)-containing interneurons of the hilus and the CA3 (Acsady et al., 1998) The interneuron-associated boutons are smaller than the giant pyramidal cell associated boutons and also have active zones (Henze et al., 2000) Notably, the average size of the active zones at these synapses is larger than the actives zones observed at other excitatory synapses in CA3, CA1, and cortex (Acsady et al., 1998),suggesting that all synapses made by the MFs pathway are relatively strong 1.1.3 Anatomic plasticity of the mossy fibers Besides the characterized structural properties summarized above, there is another unusual feature of the MFs pathway It has been revealed through anatomical techniques that the granule cells are continuously undergoing turnover throughout the life of the animal (Altman and Dascal, 1965; Angevine, 1965; Bayer, 1980; Kuhn et al., 1996; Gage, 2002) It was reported by Kaplan and Bell in 1984, that granule cells are being generated from stem cells located in the hilus continuously and the new born cells are migrating outwards into the granule cell layer Notably, the total number of granule cells apparently does not change due to the increasing age of the animal, which is regulated by genetic factor (Kempermann et al., 1997, 2006) However, there is evidence indicating that the number of granule cells is regulated dynamically by the environmental factors For example, exposure to novel or enriched environments increases the proliferation (Kempermann et al., 1998) and enlarges the MFs boutons (Gogolla et al., 2009) Strong activities such as epilepsy induced by kainite injection or kindling also affect the MFs pathway with the demonstration of the MFs sprouting (Represa and Ben-Ari, 1992a and 1992b; Wuarin and Dudek, 1996; Van-der-Zee et al., 1995) It has been reported that high-frequency stimulation induced LTP also induces MFs synaptogenesis (Adams et al., 1997; Escobar et al., 1997) Finally, the neurogenesis of the granule cell is decreasing and the appearance of the MFs synapses reduces under chronic stress (McEwen, 1999) All these findings on the neurogenesis of granule cells indicate the remodeling property of the MFs pathway 1.2 Synaptic plasticity of the mossy fibers Investigations on the MFs synaptic plasticity are carried out through patch-clamp studies on transmitter release (Henze et al., 2000) The release of glutamate and the activation of postsynaptic glutamate receptors are involved in the excitatory neurotransmission at the MFs synapses Studies have showed that the mechanism of long-lasting synaptic plasticity at mossy fibre synapses differs significantly from that at the Schaffer collateral synapse in CA1 and other typical cortical synapses (Nicoll and Schmitz, 2005) 1.2.1 Short-term plasticity Short-term plasticity at the MFs synapses onto CA3 pyramidal neurons exhibit higher level in paired-pulse facilitation (PPF) than most other synapses in the central nervous system PPF, a presynaptic form of short-term plasticity, describes the ability of synapses to increase neurotransmitter release on the second of two closely spaced afferent stimulations and depends on the residual Ca2+ concentrations in the presynaptic terminal (Nicoll and Schmitz, 2005) It has been shown that the MFs PPF is approximately two times greater in amplitude than the other CA3 commissural/associational synapses (Salin et al., 1996) Another unique property is the ability of the MFs synapses to undergo frequency facilitation, another form of short-term plasticity, in which increasing the frequency of stimulation from low to moderate (for example, from 0.05 Hz to Hz) rates can cause manifold increases in synaptic strength In contrast to the MFs synapses, CA3 commissural/associational synapses and CA1 Schaffer collateral synapses show little facilitation For example, the MFs synapses showed frequency facilitation at inter10 Quantitative analysis will be carried on the treated samples by nuclear microscopy as the way done in the study The Zn concentration in µg/g dry weight level as well as molar concentration in wet weight level in the three different strata (SL, SO and SP) of hippocampal CA3 region will be compared between the learning-treated and control animals As the result, the correlation of Zn concentration in MFs terminals and remodeling of MFs is going to be elucidated Meanwhile, further understanding will be drawn on the role of Zn in hippocampal-dependent learning and memory 7.3 Hippocampus dependent memory is impaired in heterozygous cyclin-dependent kinase knockout mice (Cdk5+/-) Intensive research efforts are required in future to elucidate the signaling pathways involved in regulating cued fear conditioning and extinction 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their locations, the. .. for the investigations on the learning- dependent morphological malleability, as well as the relations of synaptic plasticity with long-lasting memory The correlations between the basal size of the