The study by An and colleagues provides one of the first clues to an ongoing riddle. Why the already very complex pattern of multiple BDNF transcripts is further complicated by attaching the diverse mRNAs to two distinct polyadenylation signals. Making use of very elegant mouse models that were provided by colleagues in the field, the authors provide convincing evidence that mRNA versions with the longer 3'UTR are transported more efficiently into dendrites than those with the short 3'UTR tail.
Given that BDNF is an important mediator of activity-dependent synaptic plasticity, elucidating these subtle details of dendritic BDNF production and action are crucial to better understand the role of this growth factor in dementias such as Alzheimer disease. Several interesting questions arise from their important findings:
1. Data are required to show that regulated release of BDNF is affected selectively in dendrites and not in the soma, as the authors suggest.
2. The lack of dendritic BDNF protein surprisingly has a gain-of-function phenotype (increased number of dendritic...
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The study by An and colleagues provides one of the first clues to an ongoing riddle. Why the already very complex pattern of multiple BDNF transcripts is further complicated by attaching the diverse mRNAs to two distinct polyadenylation signals. Making use of very elegant mouse models that were provided by colleagues in the field, the authors provide convincing evidence that mRNA versions with the longer 3'UTR are transported more efficiently into dendrites than those with the short 3'UTR tail.
Given that BDNF is an important mediator of activity-dependent synaptic plasticity, elucidating these subtle details of dendritic BDNF production and action are crucial to better understand the role of this growth factor in dementias such as Alzheimer disease. Several interesting questions arise from their important findings:
1. Data are required to show that regulated release of BDNF is affected selectively in dendrites and not in the soma, as the authors suggest.
2. The lack of dendritic BDNF protein surprisingly has a gain-of-function phenotype (increased number of dendritic filopodia), raising the question whether dendritic TrkB receptors can exert an influence on the growth of filopodia in the absence of ligand (compare e.g., Hartmann et al., 2004). Furthermore, it would be exciting to see what would happen to synaptic function after acute, selective knockdown of dendritic BDNF mRNA using, for example, RNA interference.
3. The LTP phenotype in their BDNF (klox/klox) mice is striking. However, how can early, protein synthesis independent LTP (which is known to depend on the availability of BDNF; see e.g., Korte et al., 1995; Patterson et al., 1996) be affected in the BDNF (klox/klox) mice, if translation of dendritic BDNF mRNA to functional protein is not required for this type of plasticity? This raises the interesting question, whether the observed BDNF effect on LTP in the study by An et al. depends on reduced basal extracellular levels of BDNF at the dendrites (being in favor of a permissive effect of BDNF for LTP), or rather on reduced availability of BDNF vesicles at post-synaptic sites for activity-dependent release (stressing an instructive effect of BDNF for LTP) after tetanic stimulation (compare Hartmann et al., 2001).
4. Last, but not least, it seems possible that dendritic targeting of specific mRNAs could constitute the synaptic tag that has been postulated to steer synapse-specific modulation of LTP (compare Reymann and Frey, 2007).
Future studies that can now take advantage of these new clues reported by An et al. will hopefully help to further elucidate the effects of dendritic BDNF protein on input-specific synaptic plasticity.
References:
Hartmann M, Heumann R, Lessmann V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J. 2001 Nov 1;20(21):5887-97. Abstract
Hartmann M, Brigadski T, Erdmann KS, Holtmann B, Sendtner M, Narz F, Lessmann V. Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J Cell Sci. 2004 Nov 15;117(Pt 24):5803-14. Abstract
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: requirements, phases, 'synaptic tagging', 'late-associativity' and implications. Neuropharmacology. 2007 Jan;52(1):24-40. Abstract
Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996 Jun;16(6):1137-45. Abstract
Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8856-60. Abstract
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