Abstract 78: Fractionated whole brain irradiation modulates Homer1a expression in a brain region specific manner.

Abstract

Abstract About 500,000 new cancer patients will develop brain metastases in 2012. The primary treatment modality for ∼250,000 of these patients is partial or whole brain irradiation. While effective for controlling metastatic brain tumors, there are significant late effects (> 6 months) following radiotherapy which include a progressive, irreversible cognitive impairment. Although the exact mechanism(s) behind this radiation-induced brain injury are unknown, preclinical studies suggest that radiation alters neuronal plasticity. Indeed irradiating the rodent brain decreases long term potentiation, alters N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptor expression and ablates neurogenesis. In this study, we used microarray analysis to show that Homer1a, a transcriptionally-regulated early response gene, was transiently upregulated in the hippocampus and downregulated in the cortex at 48 hours after fractionated (total dose of 40 Gy delivered as 2 Gy/fraction, 2X/week) whole brain irradiation (fWBI) in young adult male Fischer 344 X Brown Norway rats. Two months after fWBI Homer1a gene expression was downregulated in both the hippocampus and cortex. Homer1a binds the consensus sequence on the C-terminus of the group I metabotropic glutamate receptors (mGluR); thereby, disrupting the cross-linking of constitutively expressed forms of Homer1 and activating mGluR in the absence of glutamate. Radiation did not alter phosphorylation of mGluR1, total GluR2 or phosphorylation of GluR2/3 in the hippocampus or cortex at 2 months after fWBI. However, the radiation-induced changes in Homer1a expression appeared to produce a significant downregulation in mGluR1 in the hippocampus, and a significant upregulation in the cortex. Memory/learning paradigms suggest that trafficking of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors containing mGluR1 from intracellular compartments to the plasma membrane is an “early” event during neural plasticity; thus decreased mGluR1 may result in alterations in hippocampal neural plasticity following fWBI. These data suggest a novel mechanism for the development of radiation-induced cognitive impairment. (Supported by CA122318) Citation Format: Elizabeth Moore, Mitra Kooshki, Lance Miller, Mike Robbins. Fractionated whole brain irradiation modulates Homer1a expression in a brain region specific manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 78. doi:10.1158/1538-7445.AM2013-78