A Single Aplysia Neurotrophin Mediates Synaptic Facilitation via Differentially Processed Isoforms

SummaryNeurotrophins control the development and adult plasticity of the vertebrate nervous system. Failure to identify invertebrate neurotrophin orthologs, however, has precluded studies in invertebrate models, limiting our understanding of fundamental aspects of neurotrophin biology and function. We identified a neurotrophin (ApNT) and Trk receptor (ApTrk) in the mollusk Aplysia and found that they play a central role in learning-related synaptic plasticity. Blocking ApTrk signaling impairs long-term facilitation, whereas augmenting ApNT expression enhances it and induces the growth of new synaptic varicosities at the monosynaptic connection between sensory and motor neurons of the gill-withdrawal reflex. Unlike vertebrate neurotrophins, ApNT has multiple coding exons and exerts distinct synaptic effects through differentially processed and secreted splice isoforms. Our findings demonstrate the existence of bona fide neurotrophin signaling in invertebrates and reveal a posttranscriptional mechanism that regulates neurotrophin processing and the release of proneurotrophins and mature neurotrophins that differentially modulate synaptic plasticity.Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MOV filesOptionsDownload video (36410 K)

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Canonical neurotrophin (ApNT) and Trk receptor (ApTrk) are expressed in Aplysia CNS ► ApNT and ApTrk control synaptic plasticity and growth in sensory-motor synapses ► ApNT exhibits differentially processed isoforms secreted as either mature or pro-ApNT forms ► Secreted mature and pro-ApNT forms have distinct positive synaptic functions