Neuroscience Letters 418 (2007) 143–148 Gene expression changes in the rodent hippocampus following whole brain irradiation Pragathi Achanta a,* , Kenira J. Thompson a,1 , Martin Fuss b , Joe L. Martinez Jr. a a Cajal Neuroscience Institute, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, United States b Department of Radiation Medicine, Oregon Health and Science University, OR 97239, United States Received 14 December 2006; received in revised form 6 March 2007; accepted 6 March 2007 Abstract Therapeutic cranial irradiation may result in debilitating cognitive impairments. In human patients these deficits are age and radiation dose- dependent and are attributed to a diminished capability to learn and memorize new tasks and information. Because of the known involvement of the hippocampus in memory consolidation, it is important to identify irradiation-induced changes including alterations in gene expression in this structure. Whole brain irradiation doses of 0, 0.3, 3, 10, or 30 Gray (Gy) were administered to 3-month-old rats in a single session. Twenty-four hours following cranial irradiation, hippocampi were processed for oligonucleotide microarrays analysis. Metallothioneins (MT)-I and -II, heat shock protein (Hsp-27), glial fibrillary acidic protein alpha (GFAP), and c-Fos genes were altered significantly across the various doses of irradiation. A pathway analysis shows that these genes were centered around the immediate early gene myc and tumor suppressor gene (TP53). Our results identified important genes and possible pathways that are altered in the hippocampus in the acute phase following cranial irradiation, and implicate gene pathways important for both learning and memory and apoptosis. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Cranial irradiation; Hippocampus; Gene expression; Microarray; Real-time RT-PCR Radiation of the brain, an invaluable therapeutic tool in the treatment of primary and secondary malignant brain tumors in humans, is associated with the risk for adverse side effects, including the potential for cognitive impairment. Recent studies documented a diminished capability to learn and memorize new tasks and information, as well as a reduction of full-scale IQ following irradiation [18,26]. The severity of the impairment is related to total radiation dose, irradiated brain volume and age at the time of treatment [23]. Damage of the small blood vessel endothelium with consecutive fibrosis and white matter necrosis is proposed as the potential leading cause of radiation-induced damage to normal brain tissue [7,12]. Also, direct radiation dam- age to neurons and glial structures and demyelination might contribute to radiation-induced brain toxicity. To date, there is a lack of concordance between the mech- anistic explanations of radiation-induced brain toxicity and the time patterns of the development of cognitive decline or delay in * Corresponding author. Tel.: +1 210 458 5764; fax: +1 210 458 7846. E-mail address: apragathi@utsa.edu (P. Achanta). 1 Present address: Department of Physiology, Ponce School of Medicine, P.O. Box 7004, Ponce 00732-7004, Puerto Rico. cognitive development. It is also apparent that radiation induces global changes in cerebral vasculature, as well as neural and glial damage throughout the brain [4,7]. However, there is very little information regarding the effect of radiation on areas of the brain that are related to memory formation and learning processes. In animal studies, a range of whole brain irradia- tion doses induced apoptosis in the sub-granular zone of the hippocampus, an area that provides new neurons to the dentate gyrus through neurogenesis [29]. Cranial irradiation also sig- nificantly decreases the dentate granule cell population in the hippocampus [29], and this decrease is associated with definite alterations in the microenvironment and activation of microglia [19]. Furthermore, depressed proliferative activity of precursor cells was observed acutely after irradiation, and quantitatively correlated with neurogenesis and a delayed decrease in new neuron production in the hippocampus [17,22]. This is asso- ciated with cognitive impairments in spatial learning ability and associated spatial memory in rodents [17,22]. Adult-born dentate granule neurons contribute to hippocampal-dependent learning [17,27] and are required for the formation of long-term hippocampal-based memories [28]. Thus, the hippocampus must be considered a prime target 0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.03.029