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Chapter 3.5 - Eph Receptors and Their Ephrin Ligands in Neural Plasticity

Chapter 3.5 - Eph Receptors and Their Ephrin Ligands in Neural Plasticity

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see refs. 1, 2). Their ligands, the ephrins, are also a highly abundant class of molecules.1,2 Two

main classes of Eph receptors are differentiated, A and B. This classification is based on the

homology of the extracellular domains of the receptors and on their ligand preference.3,4 EphA

receptors bind ephrinA ligands and EphB receptors bind ephrinB ligands. The ephrin ligands,

similarly to their receptors, are characterized by higher sequence homology within a class. The

A and B classes of ephrins are also different in the way these ligands are attached to the cell

membrane. EphrinA ligands are glycosylphosphatidylinositol (GPI) anchored. EphrinB ligands,

however, span the cell membrane as they possess a transmembrane and a cytoplasmic domain.

Importantly, the ephrin ligand must be membrane bound in order for it to activate its receptor.

Soluble ephrin extracellular domains are inhibitory as they bind to the Eph receptors but are

unable to initiate dimerization and autophosphorylation of the receptor. Artificial aggregation

of soluble ligands mimics the endogenous physiological conformation of the ligands and can

be used to activate the Eph receptor.5 In summary, under physiological conditions receptorligand interaction requires cell-cell contact.6

The majority of studies investigating the function of Eph receptors has been largely limited

to exploring the developmental role of these receptors.7 Interestingly, however, recently both

the receptors and their ligands were found to be expressed in the mature mammalian brain (see

e.g., ref. 9 and references therein). This has raised the intriguing possibility that Eph receptors

have a role beyond development. Here the first pieces of evidence supporting a role for Eph

kinases in the adult nervous system is reviewed. The discussion will be focused on the involvement of Eph receptors in synaptic plasticity and learning and memory. The possible mechanisms of their action will also be outlined.

Eph Receptors Are in the Right Places and at the Right Time

The expression of Eph receptors has been thoroughly investigated in the developing brain.

It has been found to be complex, temporally controlled, and tissue specific. Recently, however,

continued expression in the adult CNS has been demonstrated by in situ hybridization and

immunohistochemical analysis. For example, a strong signal for EphA5, a member of the Eph

tyrosine kinase family, was found in all hippocampal neuronal fields, in the cortex, and in the

amygdala of the adult rat brain.8 The results were confirmed in two inbred strains of mice

(C57BL/6 and DBA/2) by in situ hybridization.8 Strong EphA5 mRNA expression was observed in the hippocampus, and a milder but still clearly detectable message was seen in the

cortex, the amygdala, the thalamus and the hypothalamus.9 The presence of EphA5 protein

was also revealed.9 It was found in hippocampal tissue in a phosphorylated form, which implies

that the Eph kinase was present in an activated form in the adult mouse brain. EphrinA5, a

ligand of the EphA5 receptor, was not detected by in situ hybridization in mice.9 Nevertheless,

a more sensitive technique, quantitative real time RT-PCR demonstrated the presence of mRNA

of this and other ephrin ligands including ephrinA2.9 Other studies using immunostaining

revealed the presence of EphA3 and EphA4 receptors and the ephrinA2 ligand in both the

adult rat and mouse brains10,11 Clearly, these findings imply a possible functional role for the

Eph receptors and their ligands in the adult brain.

The mere presence of these receptors and their ligands in adult brain tissue does not allow

one to speculate what role these molecules may play there. However, analysis of their microstructural localization may offer some clues. Eph receptors and ephrinB ligands were found to

co-localize with PDZ binding proteins in subcellular fractions (crude synaptosomes, and preand post-synaptic membranes) of adult rat cortex, indicating that these molecules may be

present at synapses in vivo.12 Moreover, immunohistochemical double labeling for synaptophysin

and for Eph receptors or ephrinB ligands has confirmed synaptic localization of these proteins

in hippocampal neuronal cultures.12 Based on these observations a potential role for Eph kinases in the physiology of the synapse has been suggested,12 an idea that has gained considerable support by the results of in vivo and ex vivo analyses of the function of Eph receptors.


From Messengers to Molecules: Memories Are Made of These

Eph Receptors: “New” Players in the Adult Brain

Perhaps the first indication that Eph receptors may function in the adult brain came from a

study in which kainate induced excitotoxicity and its effects on Eph gene expression were

studied.13 Kainate injection was found to induce the expression of Eph tyrosine kinases, namely

EphA4, EphB2 and EphA5. Quantification of the expression levels of these receptors showed

significant temporal changes. The results suggested that Eph receptors/ligands might function

in neuronal pathfinding after sprouting subsequent to neuronal denervation in the adult, potentially implicating these receptors in such human brain diseases as epilepsy or spinal cord

injury.14 For instance, upon spinal cord injury EphB3 was found to be overexpressed in a rat

model of contusive spinal cord trauma suggesting that EphB3 may contribute to the unfavorable environment for axonal regeneration.68 In another study, ephrinA5 was found to be involved in selective inhibition of spinal cord neurite outgrowth and cell survival14 again suggesting that Eph receptors significantly impair regeneration after injury in the adult CNS. Another

interesting recent finding relevant for adult brain injury and repair concerns the expression of

EphB1-3 and EphA4 receptors and their ephrinB ligands in the subventricular zone (SVZ) of

the lateral ventricles in the adult mammalian brain.69 SVZ, the largest remaining germinal

zone of the adult brain contains neuroblast cells migrating rostrally to the olfactory bulb. The

Eph receptors were demonstrated to mediate the migration and proliferation of these cells69

raising the intriguing possibility that modulation of Eph receptor function may allow one to

develop therapeutic applications by influencing neurogenesis in the adult brain. Finally, in a

recent study, investigators using a kindling model found that activation or deactivation of Eph

receptors can alter the development of behavioral seizures and change both the extent and the

pattern of mossy fiber sprouting.70 In summary, it appears that Eph receptors are involved in

processes following injury to the adult brain. But what do they do in the normal brain?

Function of Eph Receptors in the Normal Brain: Role in Plasticity

and Memory

The above question has been difficult to address because of the scarcity of good molecular

tools with which one can manipulate Eph function. Specific pharmacological agents are not

available for Eph tyrosine kinases. Antisense oligonucleotide knock down approaches have not

been attempted. Gene targeting, although successfully employed with a number of Eph receptors and their ligands, has had limited use for the analysis of adult neural function because

disruption of a single gene encoding a particular receptor or ligand could be compensated for

by the presence of sister molecules. That is, functional redundancy made it difficult for the

investigators to analyze the disruption of single members of this large protein family. Another

complication in these studies is that these receptors and ligands are involved in CNS development. Thus if their disruption by gene targeting is not compensated for, the effects almost

certainly will manifest as significant developmental abnormalities which would make the analysis

of their adult neural function complicated. Perhaps, an inducible and cell type restricted knock

out approach could adequately address the confounding effects of developmental alterations.

But such an approach has not been attempted for these kinases. Furthermore, because of the

high redundancy in the Eph family (overlapping expression and high homology between sister

receptors or ligands), significant compensation may be expected if a single gene encoding one

Eph receptor or ephrin ligand is mutated15 thus double, triple, quadruple, etc. knock outs may

be needed. Ultimately, creating all permutations of absence vs. presence of the normal form of

certain members of this family may be required, clearly a daunting task that could take decades

of experimentation. To solve the above problems an alternative molecular tool, the

immunoadhesins16 was utilized.

The immunoadhesins (Fig. 1) employed in the functional analysis of EphA receptors8,9

were comprised of the ligand-binding domain of the EphA5 receptor (EphA5-IgG) or the

receptor-binding domain of the ephrin-A5 ligand (ephrinA5-IgG). These immunoadhesins

had opposing effects. EphA5-IgG scavenged the endogenous ligand and acted as an antagonist,



Figure 1. Immunoadhesins in the functional characterization of Eph receptors. Immunoadhesins (A) are

genetically engineered proteins that consist of the Fc portion of an IgG molecule attached to a cell-surface

protein (for review see 16). Immunoadhesins are disulfide-linked homodimers structurally similar to antibodies. They contain an adhesin region derived from a receptor or cell-surface ligand (triangles), the hinge

region (white rectangles) and the Fc portion (black rectangles). Immunoadhesins bind to their target (B)

with high affinity and specificity because the binding capacity of their adhesin domain is identical to that

of the receptor or ligand of interest. For example, the receptor immunoadhesin EphA5–IgG (panel B left

side) binds to ephrinA ligands anchored to the cell surface. By scavenging the ligands, it acts as a competitive

antagonist of EphA function. The ligand immunoadhesin ephrinA5–IgG (panel B right side) Fc domain,

black; receptor-binding domain of ligand attached to the Fc, “claw” shape) binds to EphA receptors (triangle

and elliptic shape) and elicits receptor dimerization, which leads to receptor activation and intracellular

signaling (but see below).

It is important to stress that these immunoadhesins recognize the ligand or the receptor on the basis of the

high-affinity ligand-receptor interaction.16,17 Immunoadhesins therefore may obviate the lack of EphA

selective pharmacological agents and, as a result of the unaltered binding sites, immunoadhesins are capable

of binding all the relevant proteins that the endogenous Eph receptor and the ephrins would bind. As Eph

receptors are promiscuous and interact with several ephrin ligands,3 immunoadhesins allow the manipulation of all functionally relevant ligands and receptors without the confounding effects of compensation

by related molecules, as occurs in gene targeting experiments.15,59,58

Several caveats must also be mentioned, however. First, the ability of immunoadhesins to act as agonists may

depend on the experimental conditions and the particular target receptor the immunoadhesin is supposed

to bind. Eliciting receptor dimerization may require cross linking several immunoadhesins, i.e., the creation

of immunoadhesin multimers.16 Second, even the monomer is large enough not to be able to cross the blood

brain barrier. Thus the in vivo delivery of the immunoadhesin requires time consuming, delicate, and

invasive stereotaxic brain surgery. Third, the immunoadhesin solution may contain endotoxin, a bacterial

lipoprotein-polysaccharide complex that may have significant toxic effects in the brain. Fourth, the

immunoadhesin, as a foreign protein, may elicit an immune response. Despite these caveats that can

complicate the interpretation of immunoadhesin effects, immunoadhesins have been successfully used in

the functional analysis of neurotrophic factors and their tyrosine kinase receptors as well as ephrins and their

Eph receptors (for a recent review and methods see refs. 60, 61). Figure modified from ref. 60.


From Messengers to Molecules: Memories Are Made of These

whereas ephrinA5-IgG worked as an EphA agonist by dimerizing and initiating the

autophosphorylation cycle of the receptor.6,17

Acute administration of EphA5-IgG, the EphA antagonist, resulted in EphA receptor deactivation leading to a significant impairment in long-term potentiation (LTP) in rat hippocampal slices.8 Conversely, the agonist immunoadhesin, ephrinA5-IgG, led to synaptic potentiation resembling LTP.8 These results provided the first direct evidence demonstrating that Eph

tyrosine kinases participate in synaptic plasticity in vitro.

The question whether similar effects may be seen in vivo has also been addressed.9,18 In

these studies, the synaptoplastic and behavioral effects of in vivo chronic (7 day long) bilateral

intrahippocampal immunoadhesin infusion were investigated. Although the induction of LTP

was found normal in hippocampal slices of C57BL/6 mice previously infused with EphA5-IgG,

the potentiated response was shown to decay faster when compared to control slices. The

synaptoplastic changes correlated with behavioral alterations. Mice that received bilateral

intrahippocampal infusion of EphA5-IgG for a week exhibited impaired T-maze spontaneous

alternation (Figs. 2 and 3) as well as disrupted context-dependent fear conditioning performance (Figs. 4 and 5.), behavioral aberrations indicative of hippocampal abnormalities.19,20,21

Thus, inhibition of EphA activity impaired neuronal plasticity, which manifested both in electrophysiological as well as behavioral tests. A potential concern could be that the impairment

was due to non-specific effects but perhaps general impairment of health or brain function.

However, the effects of ephrinA5-IgG induced Eph activation could not be explained by a

non-specific action of this immunoadhesin. When infused into the hippocampus of DBA/2

Figure 2. The T-maze Continuous Alternation Task (T-CAT). Mice are allowed to alternate between the left

and right arms of the T-maze throughout a 15-trial session. Once they have entered a particular arm, a

guillotine door is lowered to block entry to the opposite arm (checkered area). The door is removed only

after the mice have returned to the start arm, allowing a new alternation trial to be started. Alternation rate

is calculated as the ratio between alternating choices and total number of choices (50%, random choice;

100%, alternation at every trial; 0%, no alternation). Time to complete 15 choices is recorded. In addition,

several motor and posture patterns are also measured (not shown).



Figure 3. EphA receptors mediate spontaneous alternation performance in the T-maze. Infusion of EphA5IgG impairs alternation performance in C57BL/6 mice (A) while ephrinA5-IgG improves alternation

performance in DBA/2 mice (C) in the T-maze spontaneous alternation task. The changes are not related

to task completion time (B, D) indicating unaltered motor performance or motivation. Mean + standard

error are shown. Sample sizes (n) are also indicated.

mice, a strain with impaired hippocampal function,21,22,23,24 ephrinA5-IgG led to significantly

improved LTP and this improvement correlated with superior performance in both the T-maze

alternation task and the context dependent fear conditioning test as compared to control.

These results were replicated in another strain (C57BL/6) of mice with the use of modified

stimulation and testing protocols9 suggesting that the findings are robust and not unique to a

particular inbred mouse strain. Lastly, the involvement of Eph receptors in consolidation of

memory has also been demonstrated18 in a ketamine anesthesia induced retrograde amnesia

model. In this work, ephrinA5-IgG, infused after ketamine induced disruption of memory

consolidation, significantly improved cognitive performance in a hippocampus dependent

manner (Fig. 6). In conclusion, the electrophysiological and behavioral observations obtained

support a role for Eph receptors in neural plasticity in the adult mammalian brain.


From Messengers to Molecules: Memories Are Made of These

Figure 4. The fear conditioning paradigm. The paradigm has three phases: a training phase (A), a context

dependent test (B), and a cue dependent test (C). For training, mice receive 3 electric foot shocks (1 sec,

0.7 mA, indicated by the thick black bars on the bottom of the cage) each preceded by an 80 dB, 2900 Hz,

20 sec long tone cue (indicated by the black filled circle on the wall). The context test is performed in the

training chamber but no shock (thin bars) or tone (empty circle) is delivered. The cue test is carried out in

another chamber identical in size but different in visual, olfactory, and tactile cues from those of the training

chamber. Tone signals identical to the one used in training are given (black filled circle) but no shock (thin

bars) is delivered. Behavior is video-recorded and later quantified using event recording computer programs.

Behavior elements correlated with fear, primarily freezing, are measured. The timing of stimulus delivery

in each phase of the paradigm is also shown: solid black bars represent the tone, the arrows the shock, and

the gray shading the different context.

Mechanisms Mediating Eph Action: The First Working Hypotheses

Admittedly, the potential neurobiological mechanisms underlying the observed behavioral

and electrophysiological effects are speculative at this point. The findings obtained so far, however, have led to the emergence of working hypotheses that may be tested in future mechanistic

studies. The recent observation showing that Eph receptors and ephrinB ligands contain PDZ

recognition motifs and are bound and clustered by PDZ proteins at pre- and postsynaptic sites

of neuronal synapses in vitro suggests that Eph receptors are properly positioned to mediate

synaptic plasticity.12,25 Moreover, as Eph receptor and ephrin ligand binding interaction requires cell-cell contact (both the ligand and the receptor are membrane bound), Eph receptor

mediated signaling can be achieved in a highly localized manner, a crucial prerequisite in the



Figure 5. EphA receptors mediate cognitive performance in a context dependent manner in fear conditioning. The performance of EphA5-IgG infused C57BL/6 mice was significantly impaired compared to control

(CD1-IgG infused mice) in the context test (B) but not in other phases of the paradigm (A training, C cue

test). The performance of ephrinA5-IgG infused DBA/2 mice after fear-conditioning was significantly

improved (increased freezing) compared to the control animals in a context-dependent manner (D training,

E context test, F cue test). Note that both the context and the cued tests were carried out 24 hours after the

fear conditioning. Mean + standard error are shown. Sample sizes (n) are also indicated. Thin solid lines

represent the delivery of tone and the arrows the shocks. (Modified from ref. 9)


From Messengers to Molecules: Memories Are Made of These

Figure 6. EphA receptors are involved in consolidation of memory. The performance of C57BL/6 mice were

significantly disrupted by surgical anesthesia (ketamine) delivered 90 min after completion of training (A).

The retrograde amnesia is robust in the context test (B), and almost completely absent in the cue test (C).

EphrinA5-IgG infusion significantly ameliorates surgical anesthesia induced retrograde amnesia (D training, E context test, F cue test) in C57BL/6 mice. Mean + standard error are shown. Sample sizes (n) are also

indicated. Thin solid lines represent the delivery of tone and the arrows the shocks. (Modified from).18



activation/deactivation of single synapses essential for proper stimulus processing. Eph receptors may interact with a number of proteins through their PDZ binding domains that mediate

cytoskeletal processes12 and thus potentially affect a range of subcellular mechanisms influencing synaptic transmission and/or plasticity. Such mechanisms may include, for example, the

trafficking and docking of presynaptic vesicles,26 the clustering of neurotransmitter receptors,

e.g., AMPA-R and NMDA-R,27 and the formation of “perforated” synapses associated with

LTP28,29,30 and perhaps with memory formation. Interestingly, a member of the Eph family,

the EphA5 receptor, has been shown to mediate actin polymerization, and its activation by

administration of ephrinA5-IgG leads to actin depolymerization and axonal growth cone collapse in neuronal cell cultures and cortical explants.6 Depolymerization of actin, a component

of the scaffolding of the synapse, may allow the synapse to undergo plastic structural modification. Indeed, actin has been found to be a crucial component of the cytoskeleton present in

presynaptic as well as postsynaptic terminals31,32,33 and has been shown to be associated with

structural changes underlying synaptic plasticity34,31,35,32 affecting both presynaptic and

postsynapric mechanisms including paired pulse facilitation, and LTP.36 Remarkably, it has

been demonstrated that application of the EphA agonist ephrinA5-IgG, which destabilizes

actin filaments6 improves LTP. Therefore, the assumption that EphA receptor activation mobilizes the synapse by destabilizing actin filaments thus allowing the synapse to undergo structural modifications necessary for plastic changes to take place is not far fetched. Perhaps this

hypothesis may be tested by detailed electron- or confocal microscopy analyses coupled with

electrophysiological manipulation and monitoring of the synapse.

The possibility that Eph receptors play roles in cytostructural processes is consistent with

the changes that were observed in the expression of the tubulin and MAP2 (microtubule associated protein 2) genes in response to EphA5-IgG or ephrinA5-IgG treatment.9 Tubulin and

MAP2 were overexpressed as a result of EphA receptor inactivation and were underexpressed

due to receptor activation in the adult mouse hippocampus. First, these findings are compatible with the known arresting effects of ephrinA ligands on axonal and dendritic growth during

CNS development.17,6,15 Second, they are also consistent with the suggested cytostructural

role of the Eph receptors in neural plasticity: removal of the structural components tubulin and

MAP2 may be a prerequisite of plastic changes of the synapse. In the adult brain, where major

developmental alterations do not take place, transcriptional regulation of tubulin, and perhaps

other genes of cytoskeletal proteins, may subserve the development of new or altered synaptic

connections, i.e., neural plasticity as previously assumed.37,38,39

Although the above hypotheses are plausible, they are not the only possible ones. Eph receptors may also influence synaptic mechanisms via mediating adhesion processes. For example, phosphorylation of L1, a transmembrane adhesion molecule, was demonstrated following EphB2 activation,40 and disruption of L1 function by anti-L1 antibody application was

shown to impair synaptic plasticity.41 EphA receptor induced signaling via ephrinA ligands

(e.g., ephrinA5) should also be mentioned here as it was shown to increase the attachment of

neuronal cells to the extracellular matrix,42 a process that may influence synaptic plasticity.43

Furthermore, Eph receptors contain a cytoplasmic sequence motif, YEPD, that mediates

binding src non-receptor tyrosine kinases, including src and fyn.44 fyn is involved in the

phosphorylation of NMDA-R,45 a key player in LTP,46 and fyn null mutant mice exhibit

impaired spatial learning and blunted hippocampal LTP.47 src also modulates NMDA-R

function48 and plays a crucial role in LTP.49 LTP, and NMDA-R itself, has been implicated

in acquisition and consolidation of memory .50,46,51,52,19,53,54,55 Thus, src kinase mediated

synaptic plasticity may be a potential substrate of Eph action. Lastly, EphB receptors have

been shown to directly interact with NMDA receptors, a process that may influence synapse

formation and function.56

Involvement of Eph receptors in adult neural plasticity implies that Eph receptor function

must be modulated in a precise time and location specific manner. At this point, however, it is

unclear how this is achieved. Ephrin ligands, compared to their receptors, are expressed at low


From Messengers to Molecules: Memories Are Made of These

levels in the adult brain9 implying that perhaps a considerable proportion of Eph receptors is

not activated under basal conditions. It is plausible that localized induction of expression of the

ligands is the primary process that leads to receptor activation at the appropriate synaptic sites,

however, this has not been investigated. Perhaps sensitive single cell PCR techniques or expression profiling using gene arrays will be able to address this question. It is also possible that

proper clustering of the GPI anchored membrane bound or transmembrane ephrin ligands

underlies receptor activation, as at least two ligand molecules need to be in close proximity to

induce receptor dimerization and initiate the autophosphorylation process.16 Although no direct evidence has been obtained to confirm the validity of this suggestion, ephrinA5 ligands

have been found in specialized membrane rafts, called caveolae, which perhaps facilitate clustering of EphA receptors42 and eprhinB ligands.12 Activity dependent induction of EphA and

EphB receptors (e.g., EphA4, EphA5, EphB2) at the mRNA level has been demonstrated in the

hippocampus13 suggesting that transcriptional regulation of the receptors may be possible. Alternatively, or additionally, modulation of Eph receptor signaling may be achieved through the

tyrosine phosphorylation sites identified at the juxtamembrane, SAP, and kinase domains of the

Eph receptor (reviewed in refs. 1, 2). But again, the molecular components involved in such

processes are not well understood. Similarly, the downstream elements of Eph signalling are not

yet elucidated. Nevertheless, based on the binding domains identified on the Eph receptor,

downstream molecular interactions could involve numerous signaling pathways acting through

src family cytoplasmic tyrosine kinases, the RasGAP pathway, the LMW-PTP phophotyrosine

phosphatase, PI3 kinase, the Grb2, Grb10 and SLAP adaptor proteins, and several PDZ domain containing proteins including GRIP (reviewed in refs. 1, 2). Finally, signal transduction

via ephrin ligands must also be mentioned. EphrinB ligands possess a cytoplasmic domain and

have been clearly shown to transduce signals (reviewed in ref. 57) and ephrinA ligands (ephrinA5),

as already mentioned, may also be involved in signal transduction (for review see refs. 1, 2).

Concluding Remarks

The molecular cascade of events in which Eph receptors are involved, including both the

upstream and downstream elements, are far from understood. The potential neurobiological

mechanisms associated with Eph action are also highly speculative. Nevertheless, the gross

anatomical localization of Eph receptors and ephrin ligands in the adult brain, and the localization of some of these proteins at the synapse, suggest that this receptor system is involved not

only in development of the brain but also in adult neural function. This conclusion is now

supported by the findings demonstrating that significant changes occur in synaptic plasticity

following acute or chronic modulation of Eph function in hippocampal slices and that significant changes are also observed in learning and memory after chronic modulation of Eph function in vivo.

This is a promising start by all means, but much needs to be done before the exact role of

Eph receptors in adult neural function can be understood. Characterization of the signaling

pathways upstream and downstream of the Eph receptor will be a complex task given the

multitude of potential molecular interactions in which these receptors and ligands participate.

It is also not clear whether different members of the Eph receptor tyrosine kinase family have

spatially and/or temporally distinct roles in the adult brain. Inducible and cell type restricted

gene targeting or the use of immunoadhesins and perhaps novel small molecules, specific pharmacological tools to be developed for particular Eph receptors, will advance our understanding

of the actions of the Eph receptors. Ultimately, these techniques will enable us to address the

intriguing question whether the development of our brain and the development of our memories share common molecular mechanisms.




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