Multisystemic Consequences of Brain-Derived Neurotrophic Factor (BDNF) Haploinsufficiency in the SD-BDNFtm1sage Rat Model

Brain-derived neurotrophic factor (BDNF) is one of the most pleiotropic signaling molecules in mammalian biology, regulating processes ranging from neuronal survival and synaptic plasticity to metabolic homeostasis. Under physiological conditions, BDNF expression is tightly regulated; however, it may be disrupted by a variety of adverse factors, including chronic psychological stress, sleep deprivation, oxidative stress, inflammation, aging, and metabolic imbalance. Prolonged exposure to any of these factors can chronically reduce BDNF levels, contributing to numerous disorders whose systemic consequences remain difficult to define conclusively. This uncertainty arises because the available evidence is drawn from heterogeneous sources including many species, wild-type and various gene-knockout models, and pharmacological studies of differing specificity—yielding findings that are often inconsistent and difficult to compare. Consequently, the full spectrum of multisystemic effects resulting from long-term partial BDNF deficiency remains incompletely characterized. The SD-BDNFtm1sage rat line, developed by SAGE/Envigo/Inotiv using zinc finger nuclease technology, was created to fill this gap. Sprague–Dawley rats with a heterozygous genotype retain one functional allele of the Bdnf gene, resulting in a partial, permanent reduction in BDNF expression that persists throughout life. This chronic and moderate BDNF deficiency allows the animal to survive but is insufficient to maintain normal homeostasis, disrupting many physiological systems and behavioral responses. This review summarizes findings from studies using the SD-BDNFtm1sage rat line and shows that its phenotypic spectrum—susceptibility to mental disorders, sleep disturbances, metabolic abnormalities, altered nociception, and impaired neuromuscular adaptation—closely reflects the multisystemic consequences of chronic BDNF deficiency. This broad relevance makes the model particularly useful for research with potential medical applications.