ABSTRACT
Genetic inhibition of the ephrin receptor (EphA6) in mice produced behavioral deficits specifically in tests of learning and memory. Using a fear conditioning training paradigm, mice deficient in EphA6 did not acquire the task as strongly as did wild type (WT) mice. When tested in the same context 24h later, knockout (KO) mice did not freeze as much as WT mice indicating reduced memory of the consequences of the training context. The KO mice also displayed less freezing when presented with the conditioning stimulus (CS) in a separate context. In the hidden platform phase of the Morris water maze (MWM) task, KO mice did not reach the same level of proficiency as did WT mice. KO mice also exhibited less preference for the target quadrant during a probe trial and were significantly impaired on an initial reversal of the platform. These findings suggest that EphA6, in line with a number of other Eph receptors and their ephrin ligands, is involved in neural circuits underlying aspects of learning and memory.
Subject(s)
Brain/metabolism , Ephrins/metabolism , Learning Disabilities/genetics , Memory Disorders/genetics , Receptor, EphA6/genetics , Acoustic Stimulation , Animals , Avoidance Learning/physiology , Brain/physiopathology , Conditioning, Psychological/physiology , Cues , Fear/physiology , Female , Gene Expression Regulation/genetics , Learning/physiology , Learning Disabilities/metabolism , Learning Disabilities/physiopathology , Male , Maze Learning/physiology , Memory/physiology , Memory Disorders/metabolism , Memory Disorders/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neural Pathways/metabolism , Neural Pathways/physiopathologyABSTRACT
RLIP76 (RALBP1) is a glutathione-conjugate transporter that is a critical component of clathrin-coated pit-mediated endocytosis, as well as in stress responses. In cultured cells, it provides protection from stressors including heat, oxidant chemicals, chemotherapeutic agents, UV irradiation, and X-irradiation. Here, we show marked reduction in glutathione conjugate transport capacity and stepwise increase in radiation sensitivity associated with heterozygous or homozygous loss of the RLIP76 gene in mice. Survival after radiation in homozygous knockout animals was significantly shorter than either the heterozygous knockouts or the wild type. Delivery of recombinant RLIP76 to mice lacking RLIP76 via a liposomal delivery system rescued radiation sensitivity. Furthermore, treatment of wild-type mice with RLIP76-containing liposomes conferred resistance to radiation. These findings suggest that inhibiting RLIP76 could be used for sensitization to radiation during cancer therapy and that RLIP76 liposomes could be radioprotective agents useful for treatment of iatrogenic or catastrophic radiation poisoning.
