title: BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior.
abstract: The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington's disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor-TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway.
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors.forename: Dario
authors.initials: D
authors.lastname: Besusso
authors.forename: Mirjam
authors.initials: M
authors.lastname: Geibel
authors.forename: Dana
authors.initials: D
authors.lastname: Kramer
authors.forename: Tomasz
authors.initials: T
authors.lastname: Schneider
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.forename: Liliana
authors.initials: L
authors.lastname: Minichiello
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005684:Gait / Q000187:drug effects; D017353:Gene Deletion; D005917:Globus Pallidus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; C497929:Ppp1r1b protein, mouse; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020813:Receptor, trkB; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases; D003042:Cocaine