Abstract
While ephrin-B ligands and EphB receptors are expressed to high levels in the learning centers of the brain, it remains largely unknown how their trans-synaptic interactions contribute to memory. We find that EphB2 forward signaling is needed for contextual and sound-evoked memory recall and that constitutive over-activation of the receptor’s intracellular tyrosine kinase domain results in enhanced memory. Loss of EphB2 expression does not affect the number of neurons activated following encoding, although a reduction of neurons activated after the sound-cued retrieval test was detected in the auditory cortex and hippocampal CA1. Further, spine density and maturation was reduced in the auditory cortex of mutants especially in the neurons that were dual-activated during both encoding and retrieval. Our data demonstrates that trans-synaptic ephrin-B-EphB2 interactions and forward signaling facilitate neural activation and structural plasticity in learning-associated neurons involved in the generation of memories.
Highlights
While ephrin-B ligands and EphB receptors are expressed to high levels in the learning centers of the brain, it remains largely unknown how their trans-synaptic interactions contribute to memory
We show here that EphB2 receptor forward signaling is necessary for fear conditioning (FC)-induced learning and memory, with both its intracellular tyrosine kinase catalytic activity and ability to couple to PDZ domain containing proteins being important for sound-cued, hippocampal-independent memories
The role for EphB2 is strengthened by our finding that the F620D point mutation, which constitutively activates its tyrosine kinase domain leads to enhanced contextual and sound-cued memories, and is consistent with a recent report that shows optogenetic activation of this receptor leads to increased auditory FC memory[38]
Summary
While ephrin-B ligands and EphB receptors are expressed to high levels in the learning centers of the brain, it remains largely unknown how their trans-synaptic interactions contribute to memory. In addition to innate behaviors, studies of ephrin/Eph gene targeted mice using the Morris water maze[30] and classic fear conditioning (FC)[31,32,33] indicate the molecules encoded by these genes may participate in learning and memory[11,21,34,35,36,37,38] It remains unknown whether ephrin-B-EphB interactions contribute to experience-driven neuron activation or if their signaling can affect the growth and/or remodeling of spines and synapses following exposure to a specific behavioral learning task that leads to formation of a particular memory. Our data indicate that trans-synaptic ephrin-B-EphB2 interactions and forward signaling facilitate the expression of IEGs and modulate the structural plasticity of spines within neurons associated with experience-driven memories, providing a trans-synaptic signaling mechanism that controls neuronal activation and morphological changes involved in learned behavior
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