Brain-derived neurotrophic factor (BDNF) promotes serotonergic neurotransmission and the structural plasticity of serotonergic (5rHT) neurons in the adult brain. Impaired 5-HT function and decreases in BDNF have been implicated in the pathophysiology of major depression and anxiety disorders. However, 5-HT and BDNF neurotransmission may become compromised in aging and therefore play important roles in the pathogenesis of age-related neurodegenerative disorders, as well as depression. This application describes exploratory research characterizing in a BDNF deficient mouse the function of the serotonin transporter (SERT) and somatodendritic 5-HT1A autoreceptor, proteins that play a key role in regulating 5-HT neuro- transmission. BDNF () mice exhibit age-dependent structural and neurochemical deficits in central 5-HT neurons. Prior to the appearance of gross structural deficits, BDNF () mice at 3-6 months of age display region-specific abnormalities in 5-HT neurotransmission, and an attenuation of somatodendritic 5-HT1A autoreceptor function in the median but not dorsal raphe nucleus. Preliminary data indicate that SERT function in the CAS region of hippocampus is markedly attenuated in BDNF () mice at 5, but not 2 months of age when compared to wild-type mice. The techniques employed in the proposed studies, quantitative autoradiography and in vivo high-speed chronoamperometry, offer the anatomical resolution necessary for us to address the hypothesis that in BDNF deficient mice, age-dependent abnormalities in SERT or somatodendritic 5-HT1A autoreceptor function will be observed for the 5-HT neurons arising from the median raphe nucleus. As the striatum receives 5-HT projections arising predominantly from the dorsal raphe nucleus, and the hippocampus receives 5-HT projections arising predominantly from the median raphe nucleus, we will focus on these areas of brain. We will characterize the function of the somatodendritic 5- HT1A autoreceptor (Aim #1) and SERT (Aim #2) in BDNF () versus wild-type mice at three discrete ages: (i) 2 months of age, presumably before the interactive effects of BDNF gene deletion and aging would affect 5-HT function, (ii) 5 months of age, a time-point to coincide with previous studies, and (iii) 10 months of age, before a loss of 5-HT innervation to the forebrain occurs. Region-specific and age-dependent changes in BDNF protein levels will be determined in selected brain regions of wild-type and BDNF () mice (Aim #3). ? ? ?
