5.1. LEARNING AND STRUCTURAL PLASTICITY

The fundamental problem of whether learning-dependent morphological malleability is related to long-lasting memory, as originally articulated by Cajal and Hebb, remains a galvanizing issue in neuroscience. In 1906, Ramon y Cajal¹ stated that “… new pathways are established through continued branching and growth of dendritic and axonal arborizations. The hypothesis that new communication pathways … only takes place after long efforts requiring attention and reflection, as well as the reorganization of mnemonic areas” (p. 724). Hebb² espoused a similar view, noting that the increased efficacy of synapses was likely due to “growth or metabolic change” that would take place at the synapse “in one or both cells” (p. 62). While there is an emphasis on changes occurring at both the pre- (axonal) and post-(dendritic) synaptic components following learning in both passages, the question remains whether the data truly support these theories.

5.2. HIPPOCAMPAL GRANULE CELL AXON TERMINALS AND LEARNING

5.2.1. Granule Cell Mossy Fiber Anatomy

Granule cells of the dentate gyrus give rise to the mossy fiber axons^1,40 that contain the heavy metal, zinc.⁴¹ Zincergic presynaptic mossy fiber terminals are readily identified using the Timm’s staining method for heavy metals.⁴² Mossy fiber boutons synapse on large thorny excrescences of CA3 pyramidal neurons⁴⁰ and on mossy fiber-associated inhibitory interneurons.^43,44 The glutamatergic mossy fibers provide excitatory input to the apical dendrites of CA3 pyramidal cells in the stratum lucidum. CA3 pyramidal cells also receive major excitatory inputs from other CA3 neurons via recurrent collaterals^45,46 and direct cortical input from layer III of the entorhinal cortex via the perforant path.⁴⁷

Each granule cell mossy fiber makes anywhere from 10 to 18 synapses with CA3 pyramidal cells in the stratum lucidum.⁴⁸ The sparseness of the granule cell input to CA3 pyramids is highlighted when compared with the number of contacts made by a single CA3 pyramidal neuron axon that can contact 12,000 to 60,000 neighboring pyramidal neurons within the ipsilateral CA3 region.⁴⁹

5.2.1.1. Mossy Fiber Pathways and Axonal Termination Zones

As illustrated in Figure 5.1, four separate ipsilateral mossy fiber pathways terminate on CA3 pyramidal cells: the suprapyramidal (SP) mossy fiber pathway (A in Figure 5.1), the infra-intra-pyramidal (IIP) mossy fiber pathway (B), the distal stratum oriens (dSO) pathway (C) that projects to CA3 basal dendrites. and the descending longitudinal pathway (DP) of the mossy fibers (D) that projects septo-temporally to other CA3 lamella.

FIGURE 5.1

The rat hippocampus has four mossy fiber projections to CA3 pyramidal cells. The figure shows the four mossy fiber projections from granule cells (red) to CA3 pyramidal neurons (green). Note that the basal distribution of Timm’s staining used (more...)

SP pathway

This pathway is responsible for the majority of granule cell synapses on CA3 pyramids and is derived from granule cells located throughout both the internal (dorsal) and external (ventral) blades as well as the crest of the dentate gyrus.^48,50 SPMF boutons terminate in the stratum lucidum (SL) on the proximal (to the soma) 100 μm of CA3 pyramidal cell apical dendrites.⁵¹ This projection innervates CA3c through CA3a pyramidal cells, terminating at the border of CA3a at the boundary with the large pyramids of CA2.^45,50

IIP pathway

Primarily originating from granule cells of the ventral (external) blade, this pathway contacts the basal dendrites of superficial and the apical dendrites of deep-lying pyramidal cells in CA3b and CA3c.

dSO pathway

Mossy fiber terminals located in this pathway are axon collaterals and presynaptic expansions from the SP that cross the pyramidal cell layer to contact the basal dendrites of CA3 pyramidal neurons.⁵⁰ These terminals are derived from granule cells throughout the entire extent of the dentate gyrus, although it is not known whether a subset of granule cells are marked for the dSO projection only. Both the IIP and the dSO have been observed to continue to grow for well over 1 year after birth.⁴⁰

DP

While pathways A through C are arranged in a lamellar organization,^47,52 the DP courses along the longitudinal axis of the hippocampus, traveling from the granule cell layer transversely through the stratum lucidum before abruptly turning ventrally at the tip of the stratum lucidum proximal to the border with CA2.^45,50 The descending pathway then synapses on more temporally located CA3 cells,⁴⁰ sometimes traveling as far as 2 mm in the temporal direction.⁵²

5.2.1.2. Role of Mossy Fibers in Learning and Processing of Spatial Information

Much of the initial identification of the mossy fibers as important for the learning process was conducted by Dr. Hans-Peter Lipp and colleagues who focused on correlations between the basal size of the IIP and various forms of hippocampal-dependent learning.^53,54 Because hippocampal function is associated with the formation of spatial maps,⁵⁵ Lipp and colleagues investigated whether increased distribution of IIPs found in some mammals might be correlated with superior spatial learning.

Consistent with this view, the length of rat hippocampal IIP mossy fibers is positively correlated with performance on spatial navigation using the Morris water maze.⁵⁶ Similarly, differences in the distribution of the IIP pathways in various inbred strains of mice predicted performance on tests of hippocampal function.⁵⁴ For example, on two different hippocampal-dependent tasks, significant positive correlations between the extent of the IIP pathway in DBA and C57 inbred mice and task performance have been described.^57,58

Reversible inactivation of CA3 MF-terminal fields with injections of diethyldithiocarbamate (DDC) during the acquisition phase of a hidden platform water maze task-impaired retention of the platform location as shown by a lack of a spatial preference during a probe test.⁵⁹ A similar study found that the DDC-impairing effect was selective for spatial but not nonspatial water maze tasks.⁶⁰ In a spatial object recognition task, injections of DDC into the CA3 region during the acquisition phase did not affect acquisition of the task but did impair recall of the spatially displaced object.⁶¹ These data indicate a causal relationship between MF function and spatial information processing.

Although studies by Lipp and colleagues demonstrates the importance of the IIP to learning and memory, their work was primarily concerned with how anatomical differences conveyed by development and genetics correlate with cognitive differences and not with the plasticity of this or other mossy fiber pathways. Non-pathological structural plasticity of mossy fiber pathways was first demonstrated by Ramirez-Amaya and colleagues, who observed that training adult Wistar rats in the Morris water maze resulted in an increased distribution of Timm’s-stained mossy fiber terminal fields (MFTFs) in the stratum oriens (SO) sublayer of the CA3 region of the hippocampus.^62,63 The change in Timm’s staining that they reported required several days (>3) of training and persisted for at least 30 days.⁶³ Despite the implications of these results, both studies have remained largely overlooked. For example, no mention of these findings is made in two recent articles, one on cortical axonal remodeling²¹ and the other on mossy fibers.⁶⁴ Possible reasons for the obscurity of these reports include (1) the lack of replication by independent laboratories, (2) reliance upon the Timm’s stain to identify growth, (3) the implication that this growth was pathological because mossy fiber sprouting has traditionally been linked with epilepsy, and (4) lack of adequate controls to establish dependence upon hippocampal function.

Building upon the paradigm first described by Ramirez-Amaya et al.,^62,63 we subsequently found that MFTF area is indeed significantly increased in Wistar rats (WRs) trained to find a hidden platform compared to yoked swim controls that swam in the water maze for a similar amount of time but with no platform present.^65,66 Importantly, no changes in the area of MFTFs were observed in WRs trained to find a cued visible platform, which does not require the hippocampus.⁸ Thus, the learning-induced presynaptic growth that we observed 7 days after the fifth day of water maze training was a direct result of learning that specifically recruited the hippocampus. The observed growth was also independent of any stress-related responses that may have resulted from exposure to the water maze. What is more, the growth process appeared to be protracted, as we did not observe significant increments in MFTF area when animals were sacrificed 2 (rather than 7) days after the fifth day of training.⁶⁵

To confirm the presynaptic localization and mossy fiber identity of learning-specific increments in Timm’s histological staining, we immunostained hippocampal tissue from hidden platform-trained rats and swim controls for Tau and ZnT3, respectively, and found corresponding increments in immunoreactivity for both proteins in the SOs of hidden platform-trained rats.⁶⁶

We also found that another strain, Long Evans rats, learned and retained water maze tasks more rapidly than Wistar rats. To demonstrate a possible difference in mossy fiber morphology, we examined the distribution of IIP in non-trained animals and found that consistent with the findings of Lipp and others, the better-learning Long Evans strain possessed a greater basal distribution of mossy fibers. We also observed spatial learning-specific expansion of MFTFs in Long Evans rats. Interestingly, the rapidity with which Long Evans rats recalled the location of a hidden platform was reflected in their equally rapid expansion of stratum oriens MFTFs. Significant increments in learning-induced MFTF expansion were observed as soon as 24 hours after end of the fifth day of training.⁶⁶

Thus, we have demonstrated that learning can actually induce a remodeling of the presynaptic input circuitry within a specific portion of the hippocampus. Furthermore, this phenomenon is not restricted to a particular strain of rat but is found even in animals that begin training with a prominent distribution of mossy fibers (e.g., Long Evans rats). Because mossy fibers primarily terminate in the stratum lucidum (SL in Figure 5.2c), the observed learning-induced increment in the SO likely represents increased innervation of CA3 basal dendrites by granule cell mossy fiber terminals (Figure 5.2d).

FIGURE 5.2

Learning-induced expansion of mossy fiber terminal fields. (a). Cartoon of the hippocampus, demonstrating mossy fiber pathways between dentate gyrus granule cells (black/gray circles) and CA3 pyramidal neurons (white triangles). Mossy fibers primarily (more...)

Indeed, an expansion of mossy fiber terminals on the basal dendrites of CA3 pyramids may impact learning by positively influencing future encoding by increasing the granule cell input to a given pyramidal cell. Clusters of thorny excrescences on basal dendrites of CA3 neurons are located closer (27 ± 3.1 versus 77 ± 1.9 μm) to pyramidal cell bodies than clusters on apical dendrites.^67,68 Because any MF input to basal dendrites would be substantially closer to the soma than corresponding input to apical dendrites, Gonzales et al. hypothesized, using the logic outlined in Carnevale et al.,⁶⁷ that mossy fiber–basal dendritic synapses may hold greater influence over somatic voltages than mossy fiber–apical dendritic synapses.⁶⁸ Given the sparseness of mossy fiber–CA3 coding, increasing the efficacy of individual synaptic contacts would facilitate the ability of individual groups of mossy fibers to act as “detonators”⁶⁹ and thereby enhance the encoding of spatial information.⁷⁰

5.3. MECHANISMS OF PRESYNAPTIC STRUCTURAL PLASTICITY

Presynaptic structural plasticity, such as is observed in the learning-specific expansion of hippocampal MFTFs, can manifest in a number of different ways. One possibility is that prior to learning there are a number of presynaptic filopodia or “pioneer” terminals that continually seek out prospective postsynaptic partners. With sustained, correlated activity, as is presumed to take place with learning, extracellular signaling could then induce filopodial differentiation to mature, active terminals.^64,71

Another possibility is the actual learning-induced growth of presynaptic terminals. This growth can take several forms. First, there is a possibility that sustained activity results in the sprouting of new presynaptic terminals that are likely to synapse with existing dendritic spines. It is interesting to note that although learning-induced synaptogenesis could result in a net increment in the number of boutons, it does not have to result in changes in the actual density of active zones.⁷² Alternatively, an activity-induced remodeling of the presynaptic terminal is possible. This remodeling would not result in any changes in the number of terminals per se but would increase the effective number of active zones and neurotransmitter release sites. Such remodeling may be considered growth as it would require substantial cytoskeletal and intracellular remodeling.⁷³

5.4. PRESYNAPTIC DISPARITY: ANTI-BOUTONISM OR BIOLOGICAL REALITY?

Based on the literature reviewed in preceding sections, it seems worthwhile to inquire as to the reason for the strong emphasis on the role played by the postsynaptic element. It may be that presynaptic structural plasticity is a phenomenon that is specific to only a subset of axons in the mature nervous system.

Certainly the mossy fibers and their neurons of origin, dentate gyrus granule cells, can be considered a unique cellular population within the brain.⁴⁷ As one of only a few consensus neurogenic sites in the adult animal, over 9000 new neurons are produced per day in the rat dentate gyrus.^107,108 Because hippocampal-dependent learning enhances the survival of adult-derived granule cells,¹⁰⁹ the contribution of neurogenesis to learning-induced expansion of MFTFs must be considered. However, a comparison of the rapidity with which learning-induced presynaptic growth is observed in Long Evans rats with the time required for axonal extension of nascent granule cells^66,110 strongly suggests that synaptogenesis of existing terminals plays a part in learning-induced growth of mossy fiber terminals in the adult.

A more likely reason for the pre- versus postsynaptic disparity is that learning-induced growth of presynaptic terminals can also result in retraction of inactive or redundant terminals.¹¹¹ Indeed, a highly transient population of presynaptic terminals⁶⁴ would be congruent with theories of homeostatic plasticity,¹¹² suggesting that although there may be local fluctuations in the number of synapses, the total synaptic weight in a given region of the brain remains largely the same, irrespective of activity. Thus, for every increment in the number of synaptic inputs from a given cell population, there is likely a roughly equal decrement in inputs from a different source. Such mechanisms would account for the lack of quantitative data demonstrating activity-induced changes in the number of presynaptic terminals because merely measuring the number of terminals in a region of fixed neuropil would produce numbers that belie the dynamic processes taking place in living tissue.

With improved and more readily accessible application of technologies, such as 2-photon microscopy (e.g., Engert and Bonhoeffer⁶), researchers in the not-so-distant future will be able to visualize individual presynaptic terminals in vivo and study their real-time responses to activities. Indeed, the giant mossy fiber terminals may be the ideal systems for exploring this exciting possibility. Thus future studies may allow direct observation of actual presynaptic plasticity mechanisms and would provide insight into how they regulate learning and memory in vivo.¹¹³

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