Regulation of learning by EphA receptors: a protein targeting study

EphA family receptor tyrosine kinases and their ephrin-A ligands are involv ed in patterning axonal connections during brain development, but until now a role for these molecules in the mature brain had not been elucidated. He re, 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 pre sent in a phosphorylated form. Because there are no pharmacological agents available for EphA receptors, we designed recombinant immunoadhesins that s pecifically bind to the receptor binding site of the ephrin-A ligand (antag onist) or the ligand binding site of the EphA receptor (agonist) and thus t arget EphA function. We demonstrate that intrahippocampal infusion of an Ep hA antagonist immunoadhesin leads to impaired performance in two behavioral paradigms, T-maze spontaneous alternation and context-dependent fear condi tioning, sensitive to hippocampal function, whereas activation of EphA by i nfusion of an agonist immunoadhesin results in enhanced performance on thes e tasks. Because the two behavioral tasks have different motivational, perc eptual, and motor requirements, we infer the changes were not caused by the se performance factors but rather to cognitive alterations. We also find bi directional changes in gene expression and in electrophysiological measures of synaptic efficacy that correlate with the behavioral results. Thus, Eph A receptors and their ligands are implicated as mediators of plasticity in the adult mammalian brain.