Genetic Modulation of BDNF Signaling Affects the Outcome of Axonal Competition In Vivo

BACKGROUND Activity-dependent competition that operates on branch stability or formation plays a critical role in shaping the pattern and complexity of axonal terminal arbors. In the mammalian central nervous system (CNS), the effect of activity-dependent competition on axon arborization and on the assembly of sensory maps is well established. However, the molecular pathways that modulate axonal-branch stability or formation in competitive environments remain unknown. RESULTS We establish an in vivo axonal-competition paradigm in the mouse olfactory system by employing a genetic strategy that permits suppression of neurosecretory activity in random subsets of olfactory sensory neurons (OSNs). Long-term follow up confirmed that this genetic manipulation triggers competition by revealing a bias toward selective stabilization of active arbors and local degeneration of synaptically silent ones. By using a battery of genetically modified mouse models, we demonstrate that a decrease either in the total levels or the levels of activity-dependent secreted BDNF (due to a val66met substitution), rescues silent arbors from withering. We show that this effect may be mediated, at least in part, by p75(NTR). CONCLUSIONS We establish and experimentally validate a genetic in vivo axonal-competition paradigm in the mammalian CNS. By using this paradigm, we provide evidence for a specific effect of BDNF signaling on terminal-arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant.

[1]  E. S. Ruthazer,et al.  Control of Axon Branch Dynamics by Correlated Activity in Vivo , 2003, Science.

[2]  R. Reed,et al.  X Inactivation of the OCNC1 Channel Gene Reveals a Role for Activity-Dependent Competition in the Olfactory System , 2001, Cell.

[3]  K. Svoboda,et al.  Diverse Modes of Axon Elaboration in the Developing Neocortex , 2005, PLoS biology.

[4]  Barbara L. Hempstead,et al.  Regulation of Cell Survival by Secreted Proneurotrophins , 2001, Science.

[5]  P. Bartlett,et al.  Primary olfactory axons form ectopic glomeruli in mice lacking p75NTR , 2000, The Journal of comparative neurology.

[6]  R. Axel,et al.  Genetic Ablation and Restoration of the Olfactory Topographic Map , 2000, Cell.

[7]  Eric D. Hoopfer,et al.  Wlds Protection Distinguishes Axon Degeneration following Injury from Naturally Occurring Developmental Pruning , 2006, Neuron.

[8]  L. Parada,et al.  Neurotrophins are not required for normal embryonic development of olfactory neurons. , 2001, Developmental biology.

[9]  M. Saleh,et al.  Axonal Dynactin p150Glued Transports Caspase-8 to Drive Retrograde Olfactory Receptor Neuron Apoptosis , 2005, The Journal of Neuroscience.

[10]  A. Nikolakopoulou,et al.  BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo , 2005, Development.

[11]  C. Levelt,et al.  Structural plasticity in the developing visual system. , 2005, Progress in brain research.

[12]  J. McLean,et al.  Neonatal olfactory sensory deprivation decreases BDNF in the olfactory bulb of the rat. , 2001, Brain research. Developmental brain research.

[13]  Bai Lu,et al.  BDNF and activity-dependent synaptic modulation. , 2003, Learning & memory.

[14]  D. G. Herrera,et al.  Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway , 2005, The Journal of Neuroscience.

[15]  M. Karayiorgou,et al.  Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. , 2003, American journal of human genetics.

[16]  M. Coleman.  Axon degeneration mechanisms: commonality amid diversity , 2005, Nature Reviews Neuroscience.

[17]  C. Shatz,et al.  Blockade of Endogenous Ligands of TrkB Inhibits Formation of Ocular Dominance Columns , 1997, Neuron.

[18]  Petti T. Pang,et al.  The yin and yang of neurotrophin action , 2005, Nature Reviews Neuroscience.

[19]  S. Christian,et al.  Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. , 2004, The American journal of psychiatry.

[20]  Rudolf Jaenisch,et al.  Mice lacking brain-derived neurotrophic factor develop with sensory deficits , 1994, Nature.

[21]  C. Greer,et al.  Compartmental organization of the olfactory bulb glomerulus , 1999, The Journal of comparative neurology.

[22]  D. Kaplan,et al.  Axon growth inhibition: signals from the p75 neurotrophin receptor , 2003, Nature Neuroscience.

[23]  Herwig Baier,et al.  Regulation of axon growth in vivo by activity-based competition , 2005, Nature.

[24]  Marla B. Feller,et al.  Spontaneous patterned retinal activity and the refinement of retinal projections , 2005, Progress in Neurobiology.

[25]  Paresh D Patel,et al.  Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons , 2004, The Journal of Neuroscience.

[26]  Masahiko Watanabe,et al.  Critical Period for Activity-Dependent Synapse Elimination in Developing Cerebellum , 2000, The Journal of Neuroscience.

[27]  M P Stryker,et al.  Plasticity of geniculocortical afferents following brief or prolonged monocular occlusion in the cat , 1996, The Journal of comparative neurology.

[28]  M P Stryker,et al.  Rapid remodeling of axonal arbors in the visual cortex. , 1993, Science.

[29]  Liqun Luo,et al.  Axon Pruning during Drosophila Metamorphosis Evidence for Local Degeneration and Requirement of the Ubiquitin-Proteasome System , 2003, Neuron.

[30]  Y. Goda,et al.  Mechanisms of Synapse Assembly and Disassembly , 2003, Neuron.

[31]  Petti T. Pang,et al.  Cleavage of proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity , 2004, Science.

[32]  T. Imai,et al.  Developmental elimination of ectopic projection sites for the transgenic OR gene that has lost zone specificity in the olfactory epithelium , 2003, The European journal of neuroscience.

[33]  Peter Mombaerts,et al.  Postnatal Refinement of Peripheral Olfactory Projections , 2004, Science.

[34]  G. Feng,et al.  Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition , 2003, Nature.

[35]  C. Greer,et al.  Olfactory ensheathing cells promote neurite extension from embryonic olfactory receptor cells in vitro , 1999, Glia.

[36]  C. Siao,et al.  Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior , 2006, Science.

[37]  R. Jaenisch,et al.  Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system , 1992, Cell.

[38]  F. Miller,et al.  Activity Regulates Positive and Negative Neurotrophin-Derived Signals to Determine Axon Competition , 2005, Neuron.

[39]  Richard Axel,et al.  Spontaneous Neural Activity Is Required for the Establishment and Maintenance of the Olfactory Sensory Map , 2004, Neuron.

[40]  C. Greer,et al.  Postnatal development of olfactory receptor cell axonal arbors , 1998, The Journal of comparative neurology.

[41]  Michael P. Stryker,et al.  Anatomical Correlates of Functional Plasticity in Mouse Visual Cortex , 1999, The Journal of Neuroscience.