In this study we aimed to investigate whether reduced BDNF levels aggravate the susceptibility of the brain to hazardous effects of high fat diet. For this purpose, we fed BDNF heterozygous mice and wild type littermates with normal and high fat diet for 16 weeks. Concentrations of two synaptic proteins (SNAP-25 and PSD-95) and oxidative stress parameters (MDA, SOD, CAT) were evaluated in the cortex after diet period. Interestingly, body weights of BDNF heterozygous groups fed with control diet were higher than their littermates and heterozygous mice fed with HFD were the heaviest in all experimental groups. MDA levels were significantly elevated in both HFD groups (wild type and BDNF(+/-)). Synaptic markers PSD-95 and SNAP-25 markedly decreased in BDNF(+/-) group fed with HFD compared to other groups. In conclusion, we suggest that endogenous BDNF has an important and possibly protective role in diet-induced changes in the cortex.