Elucidating the role of IL-2 in the brain during development could have important implications for understanding processes involved in autoimmune diseases affecting the brain, as well as neurodevelopmental diseases such as schizophrenia. This proposal will test the hypothesis that deletion of the IL-2 gene in the CNS produces spatial learning deficits resulting from alterations in hippocampal neurodevelopment and function. IL-2 mRNA transcripts and IL-2-like immunoreactivity have been identified in rodent and human brain and IL-2 has been implicated as both a neurotrophic factor and neuromodulator. To determine how and where IL-2 works in the brain, we have cloned and sequenced the full-length cDNAs for the alpha, beta, and gamma subunits of the brain IL-2 receptor complex. Our data and the work of others show that IL-2 receptor gene expression is enriched in the hippocampal formation, which is the only brain region where specific IL-2 receptor binding has been detected. Our preliminary studies using IL-2 knockout mice are the first to demonstrate that IL-2 gene deletion produces robust impairments in spatial learning. Thus, we propose to characterize the nature of the learning impairment in IL-2 knockout mice, focusing on the effects of IL-2 gene deletion on the neurodevelopment and function of the hippocampus.
The specific aims will: 1) Characterize the neurobehavioral phenotype resulting from IL-2 gene deletion, 2) Test the hypothesis that the neurobehavioral phenotype of IL-2 knockout mice results principally from the absence of the IL-2 gene in the CNS, rather than in the periphery, and 3) Test the hypothesis that the spatial learning deficit produced by IL-2 gene deletion will be accompanied by alterations in hippocampal cytoarchitecture and neurobiology. The proposed studies will be the first to determine the consequences of the absence of IL-2 on these aspects of brain development and behavior. We believe that the proposed research is timely and will lay an essential foundation on which to build in future studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038179-02
Application #
6188202
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Nichols, Paul L
Project Start
1999-09-01
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$258,335
Indirect Cost
Name
University of Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Beck Jr, Ray D; Wasserfall, Clive; Ha, Grace K et al. (2005) Changes in hippocampal IL-15, related cytokines, and neurogenesis in IL-2 deficient mice. Brain Res 1041:223-30
Beck Jr, Ray D; King, Michael A; Ha, Grace K et al. (2005) IL-2 deficiency results in altered septal and hippocampal cytoarchitecture: relation to development and neurotrophins. J Neuroimmunol 160:146-53
Petitto, John M; Huang, Zhi; Lo, Jeannette et al. (2003) IL-2 gene knockout affects T lymphocyte trafficking and the microglial response to regenerating facial motor neurons. J Neuroimmunol 134:95-103
Cushman, Jesse; Lo, Jeannette; Huang, Zhi et al. (2003) Neurobehavioral changes resulting from recombinase activation gene 1 deletion. Clin Diagn Lab Immunol 10:13-8
Beck Jr, Ray D; King, Michael A; Huang, Zhi et al. (2002) Alterations in septohippocampal cholinergic neurons resulting from interleukin-2 gene knockout. Brain Res 955:16-23
Petitto, John M; Huang, Zhi; Hartemink, David A et al. (2002) IL-2/15 receptor-beta gene deletion alters neurobehavioral performance. Brain Res 929:218-25
Petitto, John M; Huang, Zhi; Lo, Jeannette et al. (2002) Relationship between the development of autoimmunity and sensorimotor gating in MRL-lpr mice with reduced IL-2 production. Neurosci Lett 328:304-8
Petitto, J M; Huang, Z (2001) Cloning the full-length IL-2/15 receptor-beta cDNA sequence from mouse brain: evidence of enrichment in hippocampal formation neurons. Regul Pept 98:77-87
Petitto, J M; Streit, W J; Huang, Z et al. (2000) Interleukin-2 gene deletion produces a robust reduction in susceptibility to experimental autoimmune encephalomyelitis in C57BL/6 mice. Neurosci Lett 285:66-70