Using a chemical‐induced model of dentate granule (DG) cell death, cDNA microarray analysis was used to identify gene profiles from the laser‐captured microdissected (LCM) hippocampal DG cell region versus the CA pyramidal cell layer (CA) from 21‐day‐old male CD1 mice injected with trimethyltin hydroxide (TMT; 3.0 mg/kg, i.p.). At 6 h post‐TMT, lectin + microglia displaying a reactive morphology were in contact with active caspase 3+ neurons. By 18 h, amoeboid microglia and signs of phagocytosis, and a mild astrocytic response were present in the DG. There was no evidence of IgG extravasation in the hippocampus, or cell death and glial reactivity in the CA. Atlas 1.2K Clontech array detected 115 genes changed in the hippocampus with TMT and included genes associated with immediate‐early responses, calcium homeostasis, cellular signaling, cell cycle, immunomodulation and DNA repair. Early responses localized to LCM DG samples consisted of elevations in inflammatory factors such as tumor necrosis factor‐α and receptors, as well as MIP1α, CD14, CD18, and a decrease in factors associated with calcium buffering. By 18 h, in the DG, changes occurred in transcripts associated with apoptosis, cell adhesion, DNA repair, cell proliferation and growth. In the CA, a differential level of elevation was seen in CD86 antigen, zinc finger protein 38 and DNA damage inducible transcript 3. A significant number of genes was decreased at these early time points in both hippocampal regions.