Evaluating the brain structural expression of defined genes involved in basic biological processes of neurogenesis, apoptosis or neural plasticity may facilitate the understanding of genetic mechanisms underlying spatial memory. The aim of the present study was to compare Ascl1, Casp3 and S100a6 gene expression in the hippocampus, prefrontal cortex and cerebellum of adult rats in water maze spatial memory performance. After four days training, the mean platform time (<10 s) was evidence of stable long-term spatial memory formation. Real time PCR analysis revealed a positive inter-structural correlation for S100a6/Casp gene expression between the prefrontal cortex and the cerebellum but a negative correlation for S100a6/Ascl1 transcribed genes between the prefrontal cortex and hippocampus during swimming in the active controls. However, during spatial memory performance there was only one inter-structural correlation between the prefrontal cortex and cerebellum with respect to Casp3 expression, though there were intra-structural correlations between Casp3/Ascl1 transcriptions within the prefrontal cortex and hippocampus as well as between Ascl1/S100a6 in the cerebellum. In active learners versus naive controls, the transcrption of all genes was augmented in the prefrontal cortex but Casp3 and Ascl1 were also elevated in hippocampus whilst only S100a6 increased in the cerebellum. The findings endorsed the role of the hippocampus in memory acquisition in addition to an integrative relationship with the prefrontal cortex and cerebellum. This structural and molecular configuration is important for creation of novel neural circuitry for consolidation and reconsolidation of memory trace with an involvement of coupled processes of neurogenesis, apoptosis or neural plasticity.