Regulation of Learning by EphA Receptors: a Protein Targeting Study

Abstract

EphA family receptor tyrosine kinases and their ephrin-A ligands are involved in patterning axonal connections during brain development, but until now a role for these molecules in the mature brain had not been elucidated. Here, we show that both the EphA5 receptor and its ephrin-A ligands (2 and 5) are expressed in the adult mouse hippocampus, and the EphA5 protein is present in a phosphorylated form. Because there are no pharmacological agents available for EphA receptors, we designed recombinant immunoadhesins that specifically bind to the receptor binding site of the ephrin-A ligand (antagonist) or the ligand binding site of the EphA receptor (agonist) and thus target EphA function. We demonstrate that intrahippocampal infusion of an EphA antagonist immunoadhesin leads to impaired performance in two behavioral paradigms, T-maze spontaneous alternation and context-dependent fear conditioning, sensitive to hippocampal function, whereas activation of EphA by infusion of an agonist immunoadhesin results in enhanced performance on these tasks. Because the two behavioral tasks have different motivational, perceptual, and motor requirements, we infer the changes were not caused by these performance factors but rather to cognitive alterations. We also find bidirectional changes in gene expression and in electrophysiological measures of synaptic efficacy that correlate with the behavioral results. Thus, EphA receptors and their ligands are implicated as mediators of plasticity in the adult mammalian brain.

A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke

“…Ephrin-A5 forward signaling to EphA receptors is me-diated by tetrameric or higher order cell surface EphA clustering (25,26). This is blocked by the EphA5-Fc construct (27)(28)(29)(30), as shown in the previous in vitro and in vivo studies. However, administering preclustered ephrin-A5-Fc will cluster EphA receptors, stimulate ephrin signaling, and mediate a gain of function in this growth inhibitory system within periinfarct cortex (7,27,(29)(30)(31).…”

Changes in attack behavior and activity in EphA5 knockout mice

“…The presence of a phosphorylated form of EphA5 receptor in the adult brain leads to the speculation about possible roles in synaptic plasticity (Gerlai et al, 1999). By infusing EphA5 receptor agonist/antagonist proteins into the hippocampus, Gerlai et al (1999) showed that activation of the EphA5 receptor enhances hippocampal-dependent behavioral tasks whereas the inactivation of the EphA5 receptor impairs these functions.…”

Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus

“…Importantly, we found similar spine densities in sham wildtype and ephrin-A2 -/- mice, suggesting that if present, deficits in spines are subtle in ephrin-A2 -/- mice. Although ephrin-A2 is expressed in the mouse hippocampus throughout life and has been implicated in its topographic organisation 35, 36 , to our knowledge, there is no evidence that ephrin-A2 is involved in synaptic plasticity or spine dynamics. Rather, these processes involve ephrin-A3, ephrin-A5 and members of the ephrin-B family 37 .…”