Damage to the CNS results in a complex series of molecular and cellular changes involving the affected targets and the ensuing glial reaction. The initial gene expression events that underlie these cellular responses may serve as early biomarkers of neurotoxicity. Here, we examined gene expression profiles during the initial phase of hippocampal damage resulting from systemic exposure of rats to the organometallic neurotoxicant, trimethyltin (TMT, 8.0mg/kg, i.p.). Using TMT as a neurodegeneration tool confers several advantages for evaluating molecular events associated with neural damage: 1) regional and cellular targets and time course of damage are known, 2) the blood-brain barrier is not compromised, which limits the contribution of blood-borne factors, e.g. immune, to neural injury responses and 3) known protein and mRNA signatures of TMT-induced neurotoxicity can be used as positive controls to validate novel expression events associated with exposure to this neurotoxicant. Using Affymetrix Gene Chip to assess gene expression after TMT, combined with Ingenuity Pathway Analysis, we observed changes consistent for genes known to be affected in hippocampus, while corresponding changes were not detected in cerebellum, a non-target region. In agreement with previous observations, limited changes in expression of inflammation-related genes were observed. Correlated expression profiles were found after exposure to TMT, including changes in gene ontologies associated with neurological disease, cellular assembly and maintenance, as well as signaling pathways associated with cellular stress, energy metabolism and glial activation. Selected gene changes were confirmed from each category by q-RT-PCR and immunoblot analysis. The canonical relationships identified implicate molecular pathways and processes relevant to detection of early stages of hippocampal damage in the TMT model. These observations provide new insight into early events associated with neuronal degeneration and associated glial activation that may serve as the basis for discovery and development of biomarkers of neurotoxicity.