ABSTRACT: Deficiency of activity-induced expression of brain-derived neurotrophic factor (BDNF) disturbs neurotransmitter gene expression. Enriched environment treatment (EET) ameliorates the defects. However, how BDNF deficiency and EET affect the neurotransmitter gene expression differently across ages remains unclear. We addressed this question by determining the neurotransmitter gene expression across three life stages in wild-type and activity-dependent BDNF-deficient (KIV) mice. Mice received 2-months of standard control treatment (SCT) or EET at early-life development (ED: 0-2 months), young adulthood (2-4 months), and old adulthood (12-14 months) (N = 16/group). Half of these mice received additional 1-month SCT to examine persisting EET effects. High-throughput quantitative reverse transcription polymerase chain reaction measured expression of 81 genes for dopamine, adrenaline, serotonin, gamma aminobutyric acid, glutamate, acetylcholine, and BDNF systems in the frontal cortex (FC) and hippocampus. Results revealed that BDNF deficiency mostly reduced neurotransmitter gene expression, greatest at ED in the FC. EET increased expression of a larger number of genes at ED than adulthood, particularly in the KIV FC. Many genes down-regulated in KIV mice were up-regulated by EET, which persisted when EET was provided at ED (e.g., 5-hydroxytryptamine (serotonin) transporter [5HTT], ADRA1D, GRIA3, GABRA5, GABBR2). In both the regions, BDNF deficiency decreased the density of gene co-expression network specifically at ED, while EET increased the density and hub genes (e.g., GAT1, GABRG3, GRIN1, CHRNA7). These results suggest that BDNF deficiency, which occurs under chronic stress, causes neurotransmitter dysregulations prominently at ED, particularly in the FC. EET at ED may be most effective to normalize the dysregulations, providing persisting effects later in life. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. More information about the Open Science badges can be found at https://cos.io/our-services/open-science-badges/.
