REGULATION OF AXON GUIDANCE MOLECULE GENES: RELEVANCE TO BRAIN ADAPTATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mounting evidence that Eph/ephrin proteins in adult brain of rodents may regulate synaptic function, learning, memory and adaptation to drugs, is reformulating the conventional view that these proteins function primarily in neurodevelopment. Regional expression of Eph/ephrin in adult primate brain is uncharted and we sought to map mRNA and protein expression of Ephs/ephrin family members in adult nonhuman primate brain. We focused on EphA4, EphB1 receptors and ephrin B2 ligand, as their transcripts are implicated in neuroadaptation. We now demonstrate that brains of adult old and new world monkeys express Eph/ephrin mRNA and encoded proteins. Immunocytochemical localization of EphA4 protein revealed discrete expression in caudate/putamen, globus pallidus, substantia nigra, cerebellar Purkinje cells, pyramidal cells of frontal cortices and the subgranular zone of the hippocampus. Evidence for EphA4 expression in dopamine neurons emerged from colocalization with tyrosine hydroxylase-positive terminals in striatum, substantia nigra and ventral tegmental area. Ephrin-B2 expression was found in all brain regions, but staining was weaker than EphA4. Several regions that expressed EphA4 (e.g. substantia nigra, ventral tegmental area) also expressed ephrinB2. The close proximity of ephrinB2 with EphA4 in the adult primate brain is consistent with a potential interaction of ephrinB2 and Eph receptors to modulate NMDA receptors, memory formation and other functions of brain. This information will be instrumental in clarifying the contributions of Ephs/ephrins to neuroadaptative processes mediated by addictive and therapeutic drugs.