Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects postnatal behaviors and is associated with a variety of neuropsychiatric disorders. However, the mechanisms underlying the BDNFMet variant induced dysfunctions of the central nervous system remain obscure. In order to identify the candidate genes and pathways responsible for the dysfunctions associated with this BDNF variation, we analyzed the expression of genes in the hippocampus, prefrontal cortex, and amygdala of the BDNFMet variant mice in comparison with the wild-type mice using Illumina bead microarray. Transcriptome profiling analysis revealed region-distinctive and gene-dose dependent changes of gene expression associated with the BDNFMet variant. BDNFMet variant mice exhibited altered expression of genes associated with translational machinery, neuronal plasticity and mitochondrial function based on the gene ontology (GO) annotation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the chemokine, cell adhesion, ubiquitin-proteosome and wnt signaling pathways were altered in the BDNFMet variant mice brain. Finally, the CX3CL1/CX3CR1 signaling was identified to be impaired in the hippocampus and microinjection of CX3CL1 into the hippocampus could rescue the hippocampal dependent memory deficits in BDNFMet/Met mice, indicating that CX3CL1 may be an effective treatment option for memory disorders in humans with this genetic BDNF variation. These findings will help us further understanding the molecular mechanisms involved in the BDNFMet associated behavior and neuroanatomy alternations. © 2013 Wiley Periodicals, Inc.