Modeling SERT × BDNF interactions in brain disorders: Single BDNF gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities in serotonin transporter knock-out mice

ABSTRACT There is growing clinical evidence that many psychiatric illnesses have overlapping genetic mechanisms. Understanding these mechanisms is important to the improvement of psychiatric treatment and preventions of the disorders, and animal genetic models continue to be a critical avenue of research towards these ends. As serotonin is a key neurotransmitter with important roles in normal behavioral processes and has been implicated in the pathogenesis of psychopathological conditions such as depression, anxiety, and addiction, it is a prime target for investigation in behavioral neurogenetics. The serotonin transporter (SERT) is a key brain protein that regulates the amount of serotonin that can activate the receptor. It is becoming evident that SERT interacts with brain-derived neurotrophic factor (BDNF), an important modulator of dopaminergic, cholinergic, and serotonergic neurons, which has been linked to memory function, activity, eating behavior, depression, and anxiety. The pivotal roles played by these two brain molecules have resulted in the development of numerous mutant animal models that have reduced function of SERT, BDNF, or both. Interestingly, SERT × BDNF mutant mice show numerous different behavioral phenotypes that are distinct from either SERT mutants or BDNF mutants alone, displaying phenotypes that are highly relevant to human clinical scenarios and bringing them added validity. This chapter will provide data from numerous experiments utilizing these rodent models and will explain their relevance and validity for research into the genetics of neuropsychiatric disorders.