DescriptionSocial behaviors in mammals are regulated by core neural circuits that respond to stimuli from the environment. These circuits are formed by guidance molecules and create a “map” in the brain that corresponds to sensory surface and motor effectors. Among these guidance molecules are the Eph/ ephrin family of receptor tyrosine kinases. In this study we examined the role of ephrin-A5, a ligand for the Eph receptors, in animal behavior. We found that ephrin-A5 inactivation in the mouse caused delays in the maturation of sensorimotor skills during development and defective behaviors in adult life. Specifically, ephrin-A5-/- mothers are impaired in maternal behavior in the form of nest building and pup retrieval and male null mice show severe reduction in inter-male aggression. In addition, anxiety-like behavior is reduced in both male and female null mice. An examination of the general olfactory function revealed no apparent deficit; ephrin-A5-/- mice were able to use their sense of smell to locate a flavored cereal that was buried beneath the cage bedding, they showed increased investigatory sniffs in response to new odor, and they were able to discriminate between male and female mice, suggesting that neuronal circuits that control foraging and sex discrimination are intact. However stimuli that control maternal care, inter-male aggression and anxiety may not be directed to the appropriate circuits in the null brain. We further examined molecules that have been shown to act in theses circuits such as testosterone, corticosterone, serotonin and arginine vasopressin (AVP) and found alteration in the expression of AVP in the null brain. Taken together, our studies revealed a novel role for ephrin-A5 in the development of appropriate behaviors.