Citation

Maynard KR, Hill JL, Calcaterra NE, Palko ME, Kardian A, Paredes D, Sukumar M, Adler BD, Jimenez DV, Schloesser RJ, Tessarollo L, Lu B, Martinowich K. Neuropsychopharmacology 2015; 41(8): 1943-1955.

Affiliation

Departments of Psychiatry & Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Copyright

(Copyright © 2015, Nature Publishing Group)

DOI

10.1038/npp.2015.349

PMID

26585288

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, -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 hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region-specific 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.Neuropsychopharmacology accepted article preview online, 20 November 2015. doi:10.1038/npp.2015.349.

Language: en