Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype

Abstract

Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/x mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/x heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/x mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/x mice. A significant decrease in [3 H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3 H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT 1A autoreceptors were not desensitized in BDNF +/x mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

Sex- and SERT-Mediated Differences in Stimulated Serotonin Revealed by Fast Microdialysis

“…The parameter most commonly used to assess stimulated microdialysis data is area under the curve (AUC). 3,7,17,29,32 High-K + -induced serotonin overflow peak heights and slopes were also analyzed. 33 Serotonin overflow in response to the shortest 1 min high-K + pulse was detected in all WT-M subjects, whereas 4/5 mice in both the WT-F-PE and WT-F-MD groups exhibited detectable serotonin overflow.…”

“…However, typical serotonin microdialysis sampling in vivo is on the order of 10−30 min. [2][3][4][5][6][7]10 When coupled with offline analysis, resolution as high as 2 min has been achieved for serotonin sampling. 14−18 Offline approaches often involve decreased throughput, however, due to longer analysis times.…”

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Although the effects of intracerebroventricular BDNF on 5-HT clearance arose 3 days after growth factor injection, intrahippocampal injections led to reductions in clearance within 30 minutes, suggesting engagement of rapid, posttranslational mechanisms. Interestingly, reported reduced rates of 5-HT clearance in vivo using amperometric recordings of aged mice genetically deficient for BDNF (BDNF+/2 animals) that did not correlate with changes in SERT density (although see Guiard et al, 2008, where density changes were observed), suggestive of functional modulatory pathways connecting neurotrophin and transporter, although perhaps indirect. Although clearly complexities remain in terms of how BDNF modulates SERT over time scales of minutes to months, the relationship of the BDNF/TrkB pathway and SERT function to depression and antidepressant mechanisms points to the translational potential of further studies of this interconnection (Haase and Brown, 2015).…”

Advances in behavioral genetics: mouse models of autism

“…[192][193][194] Work with mouse lines characterized by deficient Bdnf has shown that these trophic effects are important for normal serotonergic neurotransmission. [195][196][197][198][199][200] In addition, several lines of evidence have provided support for a role of Mecp2 in the regulation of activity-dependent transcription of Bdnf, 134,201,202 suggesting that alterations in 5-HT signaling could arise from deficient Mecp2 function, through dysregulation of Bdnf. Bdnf-null mice die soon after birth, but mutants have been developed with conditional disruption of Bdnf, limited to either the prenatal or postnatal period.…”

“…Interestingly, heterozygous mice with one null Bdnf allele have decreased function of the serotonin transporter in hippocampus. 195,197 Murphy et al, [208][209][210] in a series of informative studies on gene interactions, showed that deficits in Sert nulls were exacerbated when mice were bred with Bdnf heterozygous animals. Male offspring had much greater susceptibility for the more severe phenotype than female mice.…”