The normal function of the mammalian brain is regulated by complex networks of interactions between cells and molecules, which are to a con- siderable extent dependent on mechanisms of transcriptional regulation. Disruption of such interactions by neurotoxic stimuli may lead to severe forms of dementia and to other neuropsy- chiatric disorders. Therefore, critical insight into mechanisms of neuronal dysfunction may be obtained by examining global patterns of gene expression in mammalian models of neuro- toxicity. In this regard, the combined use of rat neuronal cultures and serial analysis of gene expression (SAGE) can be viewed as a general platform to enable the search for molecular tar- gets involved in neurotoxic processes. Here, we discuss potential advantages of this approach, highlighting the need for generation of robust SAGE libraries from rat neuronal cultures. The availability and current limitations of bioinfor- matics tools for SAGE data derived from rat samples is also discussed. Keywords: SAGE; Rat neuronal cultures; High- throughput analysis; Neurotoxicity; Neuroprotection The mammalian brain is a highly complex organ which coordinates many functions ranging from the control of basic physiological functions to highly evolved cognitive abilities, such as mem- ory and thinking. Such functional diversity is in part dependent on mechanisms of transcriptional regulation, since de novo mRNA synthesis is required for several neural functions (Gilliam et al. , 2000). Therefore, it is clear that a detailed understanding of the regulation of gene expres- sion in the brain, and the development of tools to modulate it, will be critical steps in the search for novel treatments for neuropathologies that disrupt normal brain functions. Studies of global gene expression in complex samples such as neural tissue are technically chal- lenging. However, the past few years have seen interesting developments in high-throughput approaches for transcriptome analysis. Partly due to its lowering costs and relative methodological sim- plicity , cDNA microarray analysis has become a popular technique for that sake. Despite its power, however, microarray analysis results are always biased to some extent by the genes that are actually represented in the particular chip utilized. Obviously , expression of specific transcripts cannot be detected F .P. Graham Publishing Co. Commentary Interrogating Global Gene Expression in Rat Neuronal Cultures Using SAGE ADRIANO SEBOLLELA a , EMMANUEL DIAS-NETO b,c and SÉRGIO T. FERREIRA a,* a Instituto de Bioquímica Médica, Programa de Bioquímica e Biofísica Celular, Universidade Federal do Rio de a Janeiro, Rio de Janeiro, RJ 21944-590, Brazil; b Laboratório de Neurociências (LIM27), Instituto de Psiquiatria, b Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-010, Brazil; c MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA. ferreira@bioqmed.ufrj.br (Submitted 26 June 2007; Revised 25 July 2007; In final form 26 July 2007) *Corresponding author: E-mail: ferreira@bioqmed.ufrj.br ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2007 FP Graham Publishing Co., www.NeurotoxicityResearch.com Neurotoxicity Research, 2007, VOL. 12(4). pp. 209-214