Regulation of brain-derived neurotrophic factor (BDNF) gene expression in discrete neuronal ensembles controls its functional impact in brain circuits that control behavior.
Stimulating BDNF production is proposed as a potential therapeutic strategy for a number of disorders, but since BDNF and its cognate receptor TrkB are widely expressed in multiple cell types and brain regions, global stimulation strategies suffer from a lack of specificity. The BDNF gene has nine 5’ untranslated region (UTR) exons, each containing a unique promoter. These promoters drive transcription of BDNF variants that contain different regulatory sequences, but encode a similar protein. Isoforms show distinct expression patterns suggesting localization in discrete circuits. Since they produce a similar protein, individual transcripts may serve similar molecular roles, but be activated in cell populations that are dedicated to distinct brain functions. This has led to the hypothesis that BDNF isoforms may have discrete, rather than redundant, roles in brain function. This BDNF transcriptional “code” would provide tight temporal and spatial control of BDNF signaling and downstream plasticity in discrete subpopulations of neurons, allowing a single cell-signaling pathway to mediate a myriad of functions. If distinct transcripts are expressed in circuits that control specific brain functions, those transcripts may represent more selective therapeutic targets.
Using mice in which we selectively disrupted BDNF expression from individual promoters, we demonstrated that “BDNF-related phenotypes” (e.g. aggression; obesity; fear extinction; reversal learning; and stress/depression susceptibility) segregate with loss of expression from distinct promoters. Our current approach uses mouse genetics in combination with molecular, cellular and systems-level techniques to define the specific role of BDNF splice variants in discrete microcircuits that control circuit activity and behavior. By quantifying expression of individual BDNF transcripts at the single cell level, we discovered that transcript-specific activation of BDNF expression occurs in discrete neuronal ensembles. To follow up on this finding, we are utilizing novel genetic tools that allow us to functionally identify and access these cells following stimulus exposure. Using these tools, we are functionally manipulating these specific neuronal ensembles to understand their contribution to in vivo brain function and behaviors that are relevant for neuropsychiatric and neurodevelopmental disorders.
Furthering our understanding of the complex regulation of BDNF at the molecular level, we identified a series of novel, evolutionarily conserved natural antisense transcripts in the BDNF locus. Our data show that expression of these antisense transcripts is highly responsive to neural activity, but have distinct activity-dependent kinetics compared with their sense BDNF counterparts. Current efforts are directed at understanding how neural activity regulates transcription of these non-coding RNAs as well as how they control expression of individual sense BDNF isoforms to contribute to the overall BDNF transcriptional “code” that controls brain function and behavior.