title: EphrinA4 mimetic peptide targeted to EphA binding site impairs the formation of long-term fear memory in lateral amygdala.
abstract: Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathologies conditions such as phobias and posttraumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). EphrinA4 and its cognate Eph receptors are intimately involved in regulating neuronal morphogenesis, synaptic transmission and plasticity. To assess possible roles of ephrinA4 in fear memory formation we designed and used a specific inhibitory ephrinA4 mimetic peptide (pep-ephrinA4) targeted to EphA binding site. We show that this peptide, composed of the ephrinA4 binding domain, interacts with EphA4 and inhibits ephrinA4-induced phosphorylation of EphA4. Microinjection of the pep-ephrinA4 into rat LA 30 min before training impaired long- but not short-term fear conditioning memory. Microinjection of a control peptide derived from a nonbinding E helix site of ephrinA4, that does not interact with EphA, had no effect on fear memory formation. Microinjection of pep-ephrinA4 into areas adjacent to the amygdala had no effect on fear memory. Acute systemic administration of pep-ephrinA4 1 h after training also impaired long-term fear conditioning memory formation. These results demonstrate that ephrinA4 binding sites in LA are essential for long-term fear memory formation. Moreover, our research shows that ephrinA4 binding sites may serve as a target for pharmacological treatment of fear and anxiety disorders.
authors.affiliation: Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Dines
authors.affiliation: 1] Sagol Department of Neurobiology, University of Haifa, Haifa, Israel [2] Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel [3] Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel [4] Center for Brain and Behavior, University of Haifa, Haifa, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Lamprecht
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology; D036385:Ephrin-A4 / Q000008:administration & dosage* / Q000235:genetics; D005239:Fear / Q000502:physiology*; D057567:Memory, Long-Term / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D036385:Ephrin-A4