Neurological Disorders

Effects of Brain-Derived IL-2 Deficiency and the Development of Autoimmunity on Spatial Learning and Fear Conditioning

Abstract

John M. Petitto, Jesse D. Cushman and Zhi Huang

Interleukin-2 (IL-2) has been implicated in neurological disorders including multiple sclerosis and Alzheimer’s disease. Peripheral IL-2 deficiency in gene-deleted mice results in T cell mediated autoimmunity that begins to develop slowly after weaning and progressively increases through adulthood. Loss of brain-derived IL-2 results in neurobiological and behavioral abnormalities, and may contribute to the development of CNS autoimmunity by modifying the neuroimmunological milieu of the brain. We have shown previously that IL-2 knockout (KO) mice have altered learning acquisition in the Morris water-maze. Hypothesizing that the learning acquisition deficits in IL-2KO would be associated largely with the loss of brain-derived IL-2, the present study sought to determine if these cognitive alterations are due to the loss the IL-2 gene in the brain and/or autoimmunity resulting from loss of the gene in the peripheral immune system. We found that SCID congenic mice (mice free of IL-2 deficiency induced peripheral autoimmunity) without brain IL-2 (two IL-2KO alleles) did not differ from SCID congenic mice with normal brain IL-2 (two WT IL-2 alleles); thus, contrary to our hypothesis, loss of brain-derived IL-2 did not affect learning acquisition in the water-maze. Compared to adult WT littermates (9 weeks), adult IL-2KO mice with autoimmunity exhibited alterations in learning acquisition in the Morris water-maze whereas younger pre-autoimmune IL-2KO mice (5 weeks) had performance comparable to younger WT littermates, suggesting that the water-maze learning deficits in IL-2KO mice were associated with the development of peripheral autoimmunity. As IL-2KO mice have cytoarchitectural alterations in the dentate gyrus, circuitry involved in the differentiation of contexts (versus places), we also compared IL-2KO mice and littermates in a contextual fear discrimination paradigm. IL-2KO mice were found to have reduced conditioned fear discrimination that was not related to age-associated autoimmunity. Together, these findings suggest that complex interactions between IL-2 deficiency in the brain and immune system may modify brain processes involved in different modalities of learning and memory.