3.1. INTRODUCTION

Learning a new behavior and acquiring information from the environment require that specific patterns of neural activity induced by experience are maintained through plasticity in specific neural networks.¹ The persistence of the acquired information depends on how long the plastic changes are preserved. It is believed that persistent forms of synaptic plasticity, including structural synaptic plasticity among others, occur in specific neuronal ensembles, in order to maintain the information in long-term memory.

Neural activity leads to a series of molecular events such as the activation of certain neurotransmitter and kinase systems, Ca2+ influx, induction of gene expression, translation and regulation of proteins, and many others that are essential to establish the plastic changes underlying long-term memory. In this chapter I will review some of the molecular events that are relevant for the persistent forms of synaptic plasticity.

3.2. EARLY SIGNALS

Throughout the process of memory consolidation, structural changes may be driven by the initial activation of one or several neurotransmitter receptors. Probably the most important excitatory neurotransmitter system for cognitive-related plasticity is the glutamatergic system. Its involvement in persistent forms of synaptic plasticity is well accepted.^2,3 During development, dendritic spines are highly motile and it has been observed that stimulation of either α-amino-5-hydroxy-3-methyl-4-isoxazole propionic acid (AMPA) or N-methyl d-aspartate (NMDA) receptors inhibit this motility.⁴

By the use of time-lapse imaging of fluorescent glutamate receptor subunits, Washburne and colleagues⁵ demonstrated that NMDA and AMPA receptor subunits are present in motile filopodia before and during synaptogenesis and the activation of this glutamatergic receptors inhibits their motility.⁶ This suggests that glutamatergic transmission is important for stabilizing synaptic contacts and also that the formation of new synapses may depend on glutamatergic-related activity.

Consistent with this interpretation, in the adult brain LTP induction alters the structure of synapses⁷ and inhibition of LTP with an NMDA receptor antagonist, D(-)-2-amino-5-phosphonovaleric acid (AP5), prevents this structural change.⁹ Behavioral studies show similar results; for example, water maze overtraining induces changes in the distribution of mossy fiber boutons in the CA3 region of the hippocampus¹⁰ and these changes are blocked by pre-treating animals with the NMDA receptor antagonist MK801.¹¹

Increased spine density in the hippocampus is observed 24 h after trace eyeblink conditioning, and again, NMDA receptor antagonists block these changes.¹² This supports the idea that glutamatergic transmission may be an important first step in the mechanisms underlying structural synaptic plasticity.

Another interesting feature of glutamatergic transmission that may be of importance for the persistence forms of memory is that the number of AMPA and NMDA receptor molecules in the postsynaptic membrane is a function of the activity history of the synapse.^13–16 The regulation of glutamate receptor density in the postsynaptic membrane has been implicated in a special form of synaptic plasticity known as synaptic scaling.^17–19 This is a homeostatic regulation, in which the strength of the synaptic inputs across the dendrite are modulated, while preserving their relative weights. This mechanism homeostatically adjust the postsynaptic dendrite to recent changes in the efficiency of the synapse, and it is required to stabilize the plastic changes in the neural network.^17,20–22 In this way, the mechanisms that regulate the endocytosis, aggregation, and trafficking of glutamate receptors in the postsynaptic membrane is involved in this persistent form of synaptic plasticity and consequently in long-term memory.

Studies of LTP using inhibitory avoidance tasks, the Morris water maze, and conditioned taste aversion indicate that the progress of memory formation requires early involvement of NMDA, AMPA, and metabotropic glutamate receptors that may be regulated by cholinergic and GABA-ergic transmission.²³

An interaction of cholinergic and glutamate receptors has been postulated. Their activity converges, as demonstrated by studies of the multiple signal transduction pathways mediated by these receptors.^24,25 It is possible that different signal transduction cascades of fast (glutamatergic) and modulatory (cholinergic) neurotransmissions are both necessary for long-term synaptic plasticity and may converge in a given neuron.²⁶ Moreover, it has been suggested that this convergent signaling may promote morphological changes in such neurons.²⁷ This led to the hypothesis of a cholinergic regulation of long-term synaptic plasticity, suggesting that cholinoceptive cells can undergo changes in their dendritic structures as a result of ACh receptor activation by inducing the degradation of MAP-2 structures.²⁷ It is suggested that such structural changes may occur during memory consolidation and may be responsible for long-term memory storage. Recently, it has been demonstrated that cholinergic receptors mediate NGF-induced excitatory synaptogenesis,²⁸ supporting the idea that ACh can be related with molecular signals leading to morphological plasticity.

Postnatal lesions of the nucleus basalis magnocellularis in rats that produce robust cholinergic deafferentations in the cortex alter the differentiation of cortical neurons and synaptic connectivity that persist into maturity and contribute to altered cognitive behavior.²⁹ In the honey bee brain, it has been observed that treatment with pilocarpine, a muscarinic agonist, induced an increase in the volume of the neuropil similar to that observed after foraging behavioral experience.³⁰ This represents some of the most direct evidence of a possible role of ACh in structural synaptic plasticity.

Other neurotransmitter systems may also contribute to triggering or modulating persistent forms of synaptic plasticity.³¹ It is possible that synergistic actions between various systems may be required to trigger long-lasting synaptic changes. Nevertheless, these initial signals may converge in certain common cellular events such as the influx of calcium and the activation of the kinase–phosphatase system among others.

3.3. CA²⁺ AND ITS TRANSDUCER

After the activation of neurotransmitter receptors, several downstream signals are triggered. Probably the most prominent signal for synaptic plasticity is calcium which has the ability to interact with the actin cytoskeletons of dendrites and through this interaction regulates structural synaptic plasticity (for review, see Oertner and Matus³²). However, after synaptic activation, the influx of calcium ions (Ca²⁺) into cells through ligand- and voltage-gated calcium channels or from internal reservoirs results in a complex set of transitory and oscillatory signals. This complex signal requires a molecular device to transform it into a more stable and perdurable message. Such a device should be capable of activating the intracellular cascades involved in the stabilization of synaptic plasticity.

The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous and broad specificity Ser/Thr protein kinase highly enriched in the central nervous system. This enzyme is highly concentrated in the post-synaptic density and is considered an important Ca²⁺ detector in the postsynaptic region.³³ The unique regulatory properties of CaMKII make it an ideal interpreter of the diversity of Ca²⁺ signals. Evidence has shown that CaMKII can interpret messages coded in the amplitude and duration of individual Ca²⁺ spikes and translate them into distinct amounts of long-lasting Ca²⁺-independent activity.³⁴

In a nonactivated state, CaMKII is auto-inhibited, but when it interacts with Ca²⁺/CaM complexes, the blockade is released. After activation, CaMKII phosphorylates other proteins but also displays an important autophosphorylation activity. When CaMKII is autophosphorylated, the dissociation rate with CaM decreases; the enzyme is able to remain active even after CaM has dissociated from it. Thus, autophosphorylation generates a constitutive active form of CaMKII able to translate a transient Ca²⁺ signal into a persistent and independent one (for review, see Cammaroto et al.³⁵). The ability of CaMKII to maintain phosphorylation activity for a prolonged period through autophosphorylation³⁶ represents an important way to sustain signaling and may have great relevance for the consolidation of long-term synaptic plasticity.

Interestingly, CaMKII mRNA is located in the dendrites and accumulates in their active regions.^37,38 It is well-known that polyribosomal complexes are selectively localized beneath postsynaptic sites in dendrites,^39,40 and their activation can be regulated by glutamatergic activity.⁴¹ The translation of CaMKII mRNA in dendrites is regulated by synaptic activity^37,38 and depends on NMDA receptor activation.⁴²

The active form of CaMKII is found in the postsynaptic density⁴³ where it interacts with different molecules important for the structures and functions of the postsynapses. The molecules include PSD-95,⁴⁴ densin-180,^45,46 F-actin,⁴⁷ and particularly the NMDA glutamate receptor.

After CaMKII is activated in the postsynaptic density, it interacts with NMDA glutamate receptors.⁴⁸ This interaction is very important because it increases CaMKII autophosphorylation and its ability to become hyperphosphorylated.⁴⁹ For this reason, CaMKII–NMDA interaction has several consequences important for synaptic plasticity. It increases the affinity of CaMKII and the NMDA receptor subunit NR2B, making this interaction to last longer.⁴⁹ It will enhance AMPA receptor conductance by phosphorylating AMPA receptors.⁵⁰ Hyperphosphorylation can also increase the period of activation by saturating local phosphatase molecules, preventing dephosphorylation.⁵¹ Finally, hyperphosphorylation of CaMKII may increase the interactions between NMDA and AMPA receptors.⁵¹ The interactions may induce the insertion of AMPA receptors into synaptic sites that already contain NMDA receptors.⁵²

These functional properties of CaMKII are highly relevant for the proposal that CaMKII may work as a memory switch, in which CaMKII activity changes between a transitory to a stable state depending on the interaction between CaMKII and the NMDA receptor.³³ Recent evidence has shown that this may indeed be the most prominent feature of CaMKII.⁵³ After stimulation CaMKII transiently translocates to the synapses where it binds the NMDA receptor at its substrate binding S-site; in this condition CaMKII activity is Ca2+/CaM-dependent, but after prolonged stimulation a persistent interaction between CaMKII and the NMDA receptor can be formed where NR2B binds at the T286-binding site, keeping the autoregulatory domain displaced and enabling Ca2+/CaM independent kinase activity.

Together, this evidence supports a crucial role of CaMKII in the persistent forms of synaptic plasticity. In agreement, induction of LTP in the CA1 region of the hippocampus is known to rapidly increase the synthesis and accumulation of CaMKII⁵⁴ and also induces its autophosphorylation activity.^55,56 Administration of Ca²⁺/CaM in the postsynapse induces synaptic potentiation and the maintenance of this potentiation depends on the activity of CaMKII.⁵⁷ Also, the induction of LTP causes the redistribution of GluR1 from intracellular pools into dendritic spines.⁵⁸ This redistribution may be important for the stability of LTP and can be mimicked by the activation of CaMKII.⁵² It is noteworthy that local translation of CaMKII protein is required for late-phase LTP,⁵⁹ which further emphasizes the central role of CaMKII in long-term synaptic plasticity.

One of the ways synaptic plasticity may persist is through structural synaptic changes. Evidence has shown that CaMKII participates in structural synaptic plasticity. The induction of LTP along with sensory stimulation promotes rapid growth of dendritic filopodia and the formation of dendritic spines and new synapses.^8,9,60 In a remarkable work using hippocampal organotypic slice cultures,⁶¹ the intracellular administration of the autophosphorylated form of CaMKII reproduced the effects of LTP by inducing filopodia growth and spine formation. The inhibition of phosphatases (which activates CaMKII) and the application of CaM in neurons produced the same effect. Consistent with these results, blocking CaMKII activity prevented LTP, filopodia growth, and spine formation.⁶¹ Moreover, CaMKIIβ (but not CaMKIIα) has strong morphogenic activity and regulates dendritic growth, filopodia extension, and synapse formation in cell cultures.⁶² Also, CaMKII mediates the effect of integrin in structural synaptic plasticity.⁶³ In vivo studies confirm that CaMKII is involved in structural synaptic plasticity. In drosophila larvae, CaMKII regulates dendritic structure by increasing the formation of dendritic filopodia.⁶⁴

CaMKII participation in structural synaptic plasticity is consistent with the idea that it plays an important role in persistent forms of synaptic plasticity and consequently most be important for long-term memory. Mutant flies expressing an inducible CaMKII inhibitor peptide presented serious learning deficits.⁶⁵ Mice expressing a constitutively active form of CaMKII independent of Ca²⁺ presented impairments of spatial and fear-motivated tasks.³⁷

Training in the Morris water maze task induces the activation of CaMKII in the hippocampus; interestingly, retention performance of this spatial memory task positively correlates with levels of CaMKII activity.⁶⁶ Frankland and colleagues⁶⁷ showed that although heterozygous mutations of CaMKII exhibited normal memory retention for contextual fear and water maze tasks 1 to 3 days after training, the animals were amnesic when tested 10 to 50 days after training, suggesting that long-term (and not short-term) memory depends on CaMKII. These data indicate that CaMKII is an important molecule whose activity can be related to persistent forms of synaptic plasticity and may play a prominent role in long-term memory formation. However, CaMKII and other molecules directly activated by second messengers such as Ca²⁺ may interact with recently transcribed genes and their protein products.

3.4. IMMEDIATE EARLY GENES

It is well accepted that long-term memory formation requires the rapid synthesis of mRNAs and their translation in proteins. Several immediately early genes (IEGs) have been identified and they include two kind of immediate early genes, the factors that regulate the transcription of other genes such as c-fos, c-jun, zif268, and Egr-3, and the so called effector IEGs such as Arc, Narp, Homer, Cox-2, and Rheb⁶⁸ that act directly upon cells to promote different effects including plastic changes.

The c-fos, c-jun, and zif268 transcription regulators IEGs are considered good candidates for the initial steps of learning inducing long-term synaptic plasticity.⁶⁹ This is because their regulatory functions are believed to trigger cascades of activity-dependent neuronal gene expression that can lead to plastic events in neurons that may be critical for memory consolidation.⁶⁹ Importantly, the patterns of activity that induce LTP can be the same as those that induce some (but not all) immediate early genes.⁷⁰ Note that zif268 expression in the hippocampus is triggered by the same pattern of activity that induces LTP.⁷⁰ This indicates that the thresholds of synaptic activation inducing the expression of some transcription regulator genes in particular regions can be closely linked to synaptic plasticity. What is also important in the study of long-term synaptic plasticity is that these genes, like c-fos, are strongly induced in the hippocampus by experimental models of epilepsy.⁷¹ This manipulation is known to produce structural changes such as mossy fiber sprouting in the hippocampus.⁷²

Kleim and colleagues⁷³ found evidence suggesting that the expression of the immediate early gene c-fos preludes the morphological changes in the cortex associated with motor skill learning. Mice with c-fos null mutations lacked the ability to present mossy fiber sprouting as result of kindling.⁷⁴ These data suggest that c-fos may be able to trigger the expression of other genes related to structural plasticity and one of such genes can be BDNF.⁷⁵ Its role in long-term synaptic plasticity will be addressed below.

Particularly interesting for the persistent forms of synaptic plasticity are the effector IEGs like Arc, Homer, and Narp. Arc (activity-regulated cytoskeleton associated protein, also called Arg 3.1) was identified in the hippocampus and cortex.^76,77 It is induced after strong cellular activity and presents a high homology to α-spectrin, and co-precipitaltes with F-actin, both of which are important cytosketetal proteins. Interestingly, the sequence of Arc presents sites for CaMKII and PKC phosphorylation.⁷⁶ The expression of Arc is rapidly induced by cellular activity and depends on NMDA glutamate-receptor activation.⁷⁶ Trophic factors such as nerve growth factor (NGF) and epidermal growth factor can also induce its expression.⁷⁶

In hippocampal and cortical cells, expression of the Arc IEG is observed after spatial behavioral experience.⁷⁸ Importantly, in these regions, the proportion of cells that present electrophysiological activity characteristic of place cell firing^79,80 during spatial exploration are the same ones that show Arc expression after the same behavioral conditions.⁷⁸ In different species and using different behaviors, the expression of Arc is observed in the regions relevant to the correspondent behavior.^81–84

One of the most interesting features of Arc is that its mRNA travels very rapidly throughout the dendrites^85,86 (~300 μm/hr) and the speed appears independent of protein synthesis. In addition, the traffic for Arc mRNA through the dendrites is selectively seen in the activated regions of the dendrite,⁸⁶ that is, LTP stimulation of the lateral entorhinal cortex produced a band of labeling for Arc mRNA in the outer molecular layer; while stimulation of the commissural projection produced a band of labeling in the inner molecular layer.^86,87 This selective localization of Arc mRNA is followed by accumulation of Arc protein in the same activated laminae. Moreover, the selective location of Arc mRNA in the activated laminae is dependent on NMDA, but not on AMPA receptor activation or protein synthesis.^39,87

Administering antisense oligonucleotides against Arc mRNA in the hippocampus negatively affected LTP maintenance and consolidation of the water maze task.⁸⁸ BDNF-induced LTP depends on the translation of Arc protein.⁸⁹ Recently, with the use of an Arc knock-out mice these observations were confirm and important additional information was added.⁹⁰ Arc knock-out mice showed normal short-term memory but clearly impaired longterm memory for several different learning tasks.⁹⁰ Also, not only LTP maintenance was impaired but also LTD.⁹⁰ These data demonstrate that the effector IEG Arc is important for long-lasting synaptic plasticity and memory formation.

The dynamics of Arc expression have introduced us to a fascinating world of orchestrated molecular events that may regulate and fine-tune the long-lasting synaptic changes that allow memory to persist. Since Arc expression is dependent on neural activity, the detection of Arc can be used to identify individual cells activated after a particular behavior. This strategy allowed the development of a new imaging method known as compartmental analysis of temporal activity using fluorescence in situ hybridization (catFISH).⁷⁸ When neural activity is observed with catFISH, recent Arc transcription is detected in the nucleus as two foci of transcription; 20 to 30 min after the initiation of Arc mRNA transcription, Arc is translocated into the cytoplasm and observed surrounding the nuclei of cells.⁷⁸ This allows us to distinguish between cells activated by recent behavior (those with Arc mRNA in the nucleus) and those activated by a behavioral event that occurred 30 min earlier (when Arc mRNA in the cytoplasm was detected). This method was used to identify groups of cells that responded to two behavioral events separated by 20- to 30-min intervals and has the power to identify brain regions that discriminate the subtle differences among behavioral conditions.^91–93

The proportion of cells that showed electrophysiological activity after exploration is ~35% in the CA1 region of the hippocampus, and the same proportion of cells expressed Arc mRNA under the same behavioral conditions.^78,94 In the CA3 region, the proportion of cells showing both electrophysiological activity and Arc expression was ~20%^94,95; the proportion in the cortex was 50%.^94,96 This indicates a close correspondence between behaviorally induced neuronal spiking and Arc mRNA expression in regions where neuronal firing patterns are associated with behavioral experience. This also shows that the detection of Arc mRNA is a reliable method to identify cells that were activated during periods of behavioral activity.

Because a high proportion of cells express Arc in response to behavioral exploration, the role of Arc in synaptic plasticity may represent a serious problem for the system if all those cells underwent synaptic plasticity and became parts of a neural ensemble that will represent the acquired information. If so, the system should rapidly saturate, limiting the amount of memory stored. The theory suggests that the ensembles of cells that store information in long-term memory may use a sparse code to be more efficient and avoid system saturation.^97,98

Some mRNAs located in dendritic compartments are regulated at the translation level by synaptic activity; translation of Arc mRNA in particular is known to be regulated at the dendritic level.⁹⁹ For this reason we thought it was possible that the translation of Arc mRNA into protein could be regulated throughout the whole cellular structure, limiting the number of cells expressing Arc protein after behavioral exploration. If that were the case, we would be able to identify the selected group of cells that will become part of the plastic neural network responsible for maintaining the information in long-term memory.

With this in mind, we performed an experiment to characterize the time course of Arc protein expression.¹⁰⁰ Animals explored a square open box for 5 min; after varying intervals, the animals explored the same space for a second 5-min exploration. Eight different intervals were used: 30, 60, 120, 180, 240, 360, 480, and 1440 min. Two groups of animals were used as controls; the animals in one group remained undisturbed in their home cages and were sacrificed at different times throughout the day matching the sacrifice times of the other groups (Caged). The second control group explored only once and was sacrificed immediately after the first exploration (5 min). The rest of the animals were sacrificed immediately after the second exploration. The tissue sections were processed for Arc protein fluorescent immunohistochemistry, Arc mRNA FISH, and a combination of both methods to identify both Arc protein and Arc mRNA in the same tissue.

The first observation was that the percentages of cells that show Arc mRNA in the nucleus 5 min after exploration matches express the proportion of cells that presented Arc protein 60 min after exploration (Figure 3.1). These results indicate that it is not through translational regulation of Arc that the system limits the number of plastic cells involved in information storage.

FIGURE 3.1

Kinetics of exploration-induced Arc protein expression in CA1, CA3, and PCx. A. Percentage of total cells showing Arc protein (induced by first exploration) in CA1, CA3, and PCx at all time points studied. All groups were exposed twice to the same environment, (more...)

Surprisingly, we found an off-line reactivation (this is an activation without further stimulation) of Arc in the CA regions and the parietal cortex 8 hours after exploration. This off-line reactivation involved only 50% of the originally activated cells. More than 80% of the cells that showed protein expression at 480 and 1440 minutes also responded to the second exploration by expressing Arc mRNA (see Figure 3.2). We interpret this as a highly specific off-line reactivation of Arc expression in a subset of the originally activated cells. The role of this reactivation is not yet clear, but it is interesting that the proportion of cells that reactivated represented only 50% of the originally activated ensemble. Although 12% of cells in CA3 and 25% in the parietal cortex comprise too a large number of cells to be considered a sparse code, this could be part of a dynamic process that reduces the number of cells involved in a long-lasting representation.

FIGURE 3.2

Arc protein is expressed in the same neurons that express Arc mRNA. A through D. Example confocal images from parietal cortex (nuclei shown in green) taken from a caged control animal. A. Animal killed 5 min after single exploration session. B. Animal (more...)

Similarly, in a recent, astonishing study using a powerful method that visualized the expression of Arc-GFP (by inserting the green fluorescent protein after the Arc promotor) in the living mouse brain,¹⁰¹ Wang and colleagues made the observation that after repeated daily stimulation with a visual stimulus of one specific orientation, the size of the Arc-GFP-expressing ensemble in the visual cortex gradually decresed.¹⁰¹ Those cells responding to one orientation the first day that responded again the next day were more likely to respond to the same stimulus on the next consecutive days; similarly, the cells that first responded to such stimuli but did not respond the next day were less likely to respond on subsequent days. This can be interpreted as evidence that the cells that kept firing together on several consecutive days had a higher probability of continuing to fire together. The lack of Arc protein does not affect this progressive decrease in the size of the activated neural ensemble, but it does significantly increase the number of activated neurons. This suggests that Arc is required to maintain a finely tuned neural network, an idea supported by other observations made in this important work, in which they found that orientation selectivity, measured by either Arc-GFP expression or electrophysiological activity, was impaired with the lack of Arc.¹⁰¹ These data suggest that also during on-line reactivation the number of plastic cells decrease which strengths the idea that this possible selection process may be a mechanism through which the system fine-tunes the neural representation that will be stored in long-term memory.

However, in response to exploration, sparse codes were observed in the dentate gyrus at all times. In this region, a very small group of cells (only ~2%) responded to exploration.^100,102,103 Interestingly, the dynamics of Arc expression were also different from those found in the CA and cortical regions. In the dentate gyrus Arc mRNA and protein are observed in the cytoplasm 30 minutes after exploration, and they continue to be present for at least 8 hours.¹⁰⁰

Preliminary data suggest that this sustained presence of Arc depends on sustained transcription of this gene, which apparently does not occur with other IEGs, and also appear to be exclusive of the dentate gyrus granule cells since pyramidal cells has not shown evidence of sustain Arc transcription. These suggest that while in the CAs and cortical regions, off-line reactivation of Arc expression may be an important component of the neural network required to accomplish the plastic changes related to long-term memory formation, in the dentate gyrus, a sustained transcription of Arc may perform the plastic job.

A recent group of highly relevant papers from Dr Paul Worley’s and other’s laboratories had shown what exactly the role of Arc protein in synaptic plasticity can be. Chowdhury’s and colleagues work¹⁰⁴ show that Arc regulates the trafficking of glutamate AMPA receptors by interacting with dynamin 2 and endophilin 3. This highly specific interaction of Arc with the above mentioned molecules modulates the endocytosis of AMPA glutamate receptors.¹⁰⁴ This mechanism allows Arc to mediate synaptic scaling by regulating the density of AMPA GluR2 receptors in the membrane¹⁰⁵ which consequently specifically modulates AMPA mediated synaptic currents.¹⁰⁶ This suggests that synaptic scaling is one important mechanism by which Arc modulates the stabilization of synaptic plasticity and long-term memory consolidation.^88–90

Also, an important link between Arc and CaMKII exists. We were interested in studying the cell types that are able to express Arc. We found that only neurons (and not glia) are able to express Arc after behavioral stimulation or after maximal electrical stimulation. Interestingly, all the cells that express Arc under both stimulation conditions were also CaMKII-positive cells. In regions such as the hippocampus and cortex; they are considered excitatory principal cells. However, the principal cells in the striatum are GAD65/67-positive and interestingly they were also CaMKII-positive and Arc-expressing cells after exploration.¹⁰⁴ This suggests an important interaction between two plasticity-related molecules such as Arc and CaMKII.

Preliminary observations using fluorescence resonance energy transfer in culture neurons indicated that Arc and CaMKII proteins interact only in the dendrites.¹⁰⁸ This interaction may have important implications for plasticity in local dendrites. In agreement, it has been shown that Arc interaction with CaMKII in neuroblastoma cells can promote neurite outgrowth,¹⁰⁹ suggesting that this interaction may induce structural plasticity in dendritic compartments. If it occurs in adult mammalian neurons, this interaction between Arc and CaMKII may be associated with structural synaptic plasticity and could explain the actions of other important plastic related molecules such as the trophic factors that have also been shown to induce Arc expression.⁷⁶

3.5. TROPHIC FACTORS

Neurotrophins are regulatory factors known to be involved in cell development, survival, and repair. One of their most interesting features is their role in neural plasticity. The neurotrophin family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins 3 and 4 (NT3 and NT4), and two other members recently were found in fish NT6 and NT7.¹⁰⁷ Each neurotrophin has been shown to promote neurite outgrowth by responsive neurons via in vitro or in vivo studies.¹¹¹

BDNF is known to regulate the development of connections¹¹² and the complexities and sizes of dendrites¹¹³ in the cerebral cortex. The involvement of BDNF in synaptic plasticity has been suggested for a long time and is known to regulate glutamatergic activity by increasing NMDA receptor phosphorylation.¹¹⁴ During development, BDNF regulates neuronal proliferation, neuronal migration, axon path finding, dendritic growth, synapse formation, and maintenance of the synaptic contact.¹¹⁵ Interestingly, BDNF can be of great importance for learning-induced structural plasticity, particularly because its important role in spatial memory formation has been shown.¹¹⁶ Animals that underwent Morris Water maze training increased the expression of both BDNF mRNA and the BNDF receptor TrkB in the hippocampus.^116–118 This expression is observed only after several days of training, but not before.¹¹⁷ That is, when animals were trained for 1, 3, or 6 days, reaching an asymptotic level of performance at day 6, an increase in BDNF mRNA expression, measured by in situ hybridization, was observed only in animals trained for 3 and 6 days but not in the animals trained for 1 day.¹¹⁷ This interesting result resembles our previous observations^10,11 in which animals over-trained for 4 to 5 days in the Morris water maze task showed an increase in the density of mossy fiber boutons in the stratum oriens of the CA3 hippocampal region.¹¹ The coincidences of BDNF expression after water maze training and our observation regarding mossy fiber sprouting are remarkable and suggest that BDNF could be part of the molecular mechanisms that underlie spatial learning-induced structural plasticity in the hippocampus. Accordingly, it has been demonstrated that blockade of BDNF mRNA or its protein product¹¹⁹ produced spatial memory impairments.¹¹⁶

The features of BDNF make it a prominent regulator of the persistent forms of synaptic plasticity. However, it does not act alone and interacts with other molecules mentioned above. For example, it has b een observed that BDNF induces the synthesis of Arc in synaptoneurosomes.¹²⁰ BDNF induction of LTP depends on Arc protein translation.¹²¹ These data suggest an important role of Arc in BDNF-induced synaptic plasticity.

An interaction between BDNF and CaMKII has also been observed. In cultured neurons using a GFP reporter of CaMKII, BDNF induced the translation of CaMKII in dendritic spines.¹²² Based on these data, Braham and Messaudi suggested that CaMKII, Arc, and BDNF may interact in dendrites to mediate long-term synaptic plasticity. They proposed that Arc should have a mechanism to consolidate its plastic effect in dendrites.

We obtained evidence that Arc may achieve this in two ways: (1) via the offline reactivation of Arc in which the ensemble of cells is reduced progressively and (2) the sustained transcription of Arc — a reaction that apparently occurs only in dentate gyrus granule cells. Both mechanisms may interact with CaMKII, Ca²⁺ influx, and other events triggered by NMDA receptor activation that, when occurring at the time of TrKb activation by BDNF, may promote the stable plastic changes underlying memory formation.

3.6. CONCLUSIONS

The evidence review in this chapter show that the interactions between glutamate-receptor activation, CaMKII autophosphorylation activity, Arc-expression and BDNF activation of TrKb receptors are some of the cellular events associated with persistent forms of synaptic plasticity, such as synaptic scaling and structural synaptic changes.

After a behavioral situation that promote long-term memory formation, glutamatergic transmission can stimulate NMDA receptor activation and trigger Ca2+ influx into the cell, which generates a complex signal. This signal, in turn, can be translated through CaMKII which by switching between a transitory to a long-term activation that may promote long-lasting effects. Ca2+ along with other molecules such as MAPK, can regulate the expression of Arc123. After the induction of Arc expression, its mRNA will travel to the activated regions of dendrites where it can be locally translated. The dynamics of Arc expression can maintain the presence of Arc for prolonged periods of time.¹⁰⁰ The activation of TrKb receptors by BDNF will only happen after a prolonged period of training¹¹⁸ and when this activation converges with NMDA-receptor activation, it will enhance CaMKII activity. When these events coincide with the presence of Arc in dendrites, the interaction can promote long-term synaptic plasticity.

Although it is well accepted that synaptic plasticity in specific group of cells determines the stabilization of the cell assemblies that will maintain the patterns of neural activity that represent an episode, we have not yet identify the individual neurons that constitute this neural ensembles. Our current methods and new technical developments will allow us to identify precisely the individual neurons that are part of the long-term representing ensemble by identifying which neurons activate plastic related molecules and in which of them this molecules act as a molecular long-term memory switch, as suggested for CaMKII. We believe that the immediate early gene Arc is another crucial candidate for the long-term neural ensembles, because Arc is important for synaptic plasticity and its dynamics has shown an apparent selection process. We now need to completely characterize the decrease in the size of the Arc-expressing ensemble during off-line or on-line reactivation, in order to identify reliably these possible selected groups of cells, in which persistent forms of synaptic plasticity may occur. These include structural synaptic changes, such as changes in the structural features of the existing dendrites, increased density and distribution of spines, and the generation and stabilization of new synaptic contacts; also, the cells that belong to the plastic cell assemblies will be subjected to synaptic scaling of AMPA receptors and/or other persistent forms of synaptic plasticity. By characterizing the persistent forms of synaptic plasticity in the selected groups of cells we will be able to identify the plastic neural networks underlying long-term memory formation.

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