Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

Abstract

Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, regionspecific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions.

Genetics of Aggression in Alzheimer’s Disease (AD)

“…Aβ peptides indirectly affect BDNF signaling at synapses by interfering with its axonal transport in part via interaction with the TrkB receptor (Durany et al, 2000; Tanila, 2017). That BDNF expression is associated with multiple independently-regulated promoters suggest that this unique genomic structure may provide flexibility to regulate BDNF signaling in distinct cell types and circuits that serve distinct molecular functions some of which may be involved in aggressive behaviors (Spalletta et al, 2010; Faria et al, 2014; Maynard et al, 2016). It is interesting to speculate that episodic or oscillatory forms of BDNF expression in AD may correlate with aggressive outbreaks or contribute to them via complex neurotrophic signaling pathways that are known to impact behavioral phenotype.…”

Social instigation and repeated aggressive confrontations in male Swiss mice: analysis of plasma corticosterone, CRF and BDNF levels in limbic brain areas

“…45 In both rodents and humans, BDNF disruption is associated with neurobehavioral alterations and psychiatric disorders. 44 …”

“…35,[39][40][41][42][43] The present study tested the hypothesis that BDNF may underlie, at least in part, experience-induced neuroplasticity in resident mice exposed to repeated sessions of agonistic interactions. BDNF is a molecule involved in the regulation of diverse biological functions, ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult 44 ; it has also been demonstrated to be a critical mediator of changes in social motivation. 45 In both rodents and humans, BDNF disruption is associated with neurobehavioral alterations and psychiatric disorders.…”

New Insights into the Biology of the BDNF Transcriptional ‘Code’

“…In this context, in this issue, a study by Maynard et al (2016) addresses this question through the elegant and comprehensive analyses of four newly generated BDNF mouse lines with selective loss of individual BDNF promoters utilizing the previously established knock-in strategy of replacing individual exons with a GFP-STOP cassette. They examined whether different transcripts are related to specific BDNF-dependent phenotypes with these four mouse lines (Bdnf-e1, -e2, -e4, and -e6 mice) in which BDNF production is selectively impaired from each of the four major promoters (I, II, IV, or VI).…”

“…Future studies utilizing the Bdnf-e1 and -e2 mice will be informative in identifying the impact of these transcripts on specific cell types within the hypothalamus. More broadly, this study by Maynard et al (2016) introduces a valuable set of BDNF-related tools to begin to systematically dissect the in vivo impact of the individual BDNF promoters on discrete neuronal populations as well as circuits. Such future investigations may provide insights into how so many behavioral alterations initially observed in the global BDNF knockout mice can be understood through the framework of the complex BDNF transcriptional 'code'.…”