Abstract

Brain-derived interleukin-2 (IL-2) has been implicated in diseases processes that arise during CNS development (e.g., autism) to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer’s disease). Progress has been limited, however, because the vast majority of current knowledge of IL-2’s actions on brain function and behavior is based on the use exogenously administered IL-2 to make inferences about the function of the endogenous cytokine. Thus, to identify the cell-type(s) and regional circuitry that express brain-derived IL-2, we used B6.Cg-Tg/ IL2-EGFP17Evr (IL2p8-GFP) transgenic mice, which express green fluorescent protein (GFP) in peripheral immune cells known to produce IL-2. We found that the IL2-GFP transgene was localized almost exclusively to NeuN-positive cells, indicating that the IL-2 is produced primarily by neurons. The IL2-GFP transgene was expressed in discrete nuclei throughout the rostral-caudal extent of the brain and brainstem, with the highest levels found in the cingulate, dorsal endopiriform nucleus, lateral septum, nucleus of the solitary tract, magnocellular/gigantocellular reticular formation, red nucleus, entorhinal cortex, mammilary bodies, cerebellar fastigial nucleus, and posterior interposed nucleus. Having identified IL-2 gene expression in brain regions associated with the regulation of sensorimotor gating (e.g., lateral septum, dorsal endopiriform nucleus, entorhinal cortex, striatum), we compared prepulse inhibition (PPI) of the acoustic startle response in congenic mice bred in our lab that have selective loss of the IL-2 gene in the brain versus the peripheral immune system, to test the hypothesis that brain-derived IL-2 plays a role in modulating PPI. We found that congenic mice devoid of IL-2 gene expression in both the brain and the peripheral immune system, exhibited a modest alteration of PPI. These finding suggest that IL2p8-GFP transgenic mice may be a useful tool to elucidate further the role of brain-derived IL-2 in normal CNS function and disease.

Highlights

  • Research has implicated both peripheral immune and brain-derived interleukin-2 (IL-2) in neurologic disease processes that arise during CNS development to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer’s disease) [1]

  • Future studies with this mouse model can determine if glial cell activation in vivo via LPS or hypoxic damage is required to induce IL-2 expression by endogenous brain glial cells, and clarify whether IL-2 expression by glia cell cultures may be due to the process of producing primary cultures from fetal brain tissue

  • The distribution and enrichment of in situ IL-2 receptor gene expression in the septohippocampal system and related limbic regions corresponds with IL2-green fluorescent protein (GFP) transgene expression in IL2p8-GFP mice [11,12]

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Summary

Introduction

Research has implicated both peripheral immune and brain-derived interleukin-2 (IL-2) in neurologic disease processes that arise during CNS development (e.g., autism) to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer’s disease) [1]. It is widely appreciated, for example, that exogenously administered IL-2 has neuromodulatory actions ranging from neurotrophic effects on septohippocampal neurons in culture [2,3] and neurotransmitter release from cholinergic neurons [4,5], to hippocampal long-term potentiation [6] and age-related changes in learning and memory [7]. There is no reliable method to track IL-2 mRNA expression in situ in the brain to elucidate further the role of brain-derived IL-2 in CNS function and disease

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