BDNF–TrkB signaling in striatopallidal neuronscontrols inhibition of locomotor behavior

摘要

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidalneurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairmentin brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin(mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington’sdisease. Although several studies have confirmed a link between altered cortical brainderivedneurotrophic factor signaling and striatal vulnerability, it is not known whether theeffects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whetherthey are direct or indirect. Using a novel genetic mouse model, here, we show that selectiveremoval of brain-derived neurotrophic factor–TrkB signaling from enkephalinergic striataltargets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This isassociated with dopamine D2 receptor-dependent increased striatal protein kinase C andMAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergicneurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neuronscontrols inhibition of locomotor behavior by modulating neuronal activity in response toexcitatory input through the protein kinase C/MAP kinase pathway.