Upon reaching its target, an axon differentiates to form synaptic connections. Remarkably, recent studies have revealed that proteins initially identified as axon guidance cues are re-emerging as regulators of synaptic plasticity in the adult brain. Canonical axon guidance proteins such as semaphorins, ephrins, and slits, and the prototypical myelin-associated inhibitors of axon regeneration, MAG, Nogo, and OMgp, have been found to influence circuit remodeling and synaptic plasticity in the mature nervous system (Mironova and Giger, 2013). Following a study by Horn et al (2013), the netrin receptor DCC now joins this list.
Mechanisms that direct neural development have long been suggested to regulate plasticity in the mature brain. Cajal’s (1911) proposal that chemotropism might direct axon extension in the embryo included a hypothesized attractant for commissural axons secreted by floor plate cells in the embryonic spinal cord. In a stunning act of prescience, Cajal (1911) suggested that his putative chemoattractant might also influence synaptic plasticity and learning and memory: ‘The ability of neurons to grow in an adult and their power to create new associations can explain learning.’ He speculated that ‘the mechanisms are probably chemotactile like the ones we observed during histogenesis of the spinal cord’ .
Netrins were the first identified floor plate-derived axonal chemoattractants (Lai Wing Sun et al, 2011). Although shown to regulate synaptogenesis during development in Caenorhabditis elegans and Drosophila melanogaster, a role for netrins at synapses in the mature vertebrate CNS had not been investigated. Horn et al (2013) report that netrin-1 and its receptor DCC are present at synapses in the adult mouse brain, with DCC enriched in the post-synaptic density. As conventional DCC null mice die at birth, in order to study DCC function in the mature CNS, Horn et al (2013) developed a cre-lox conditional DCC knockout to delete DCC only from neurons in the mature mouse forebrain. Following the loss of DCC, dendritic spines were found to shrink, indicating that DCC maintains normal synaptic morphology. Furthermore, DCC activation of the cytoplasmic tyrosine kinase Src was shown to be required for NMDA receptor-dependent long-term potentiation, a form of activity-dependent synaptic plasticity, and for certain forms of learning and memory.
Earlier studies found that conventional adult DCC heterozygous mice, which express reduced levels of DCC protein, exhibit a blunted response to amphetamine and fail to sensitize to repeated doses (Flores et al, 2005), a form of plasticity thought to influence drug addiction. The findings provided by Horn et al (2013) raise the possibility that deficient NMDA receptor function in DCC heterozygotes may contribute to defective sensitization. Flores et al (2005) also drew similarities between the sensitization defects and models of neural dysfunction in schizophrenia, and NMDA receptor hypofunction has been proposed as an underlying deficit in schizophrenia (Coyle, 2006). Intriguingly, recent reports describe single-nucleotide polymorphisms in the human DCC gene associated with schizophrenia, Parkinson’s disease, and amyotrophic lateral sclerosis. Ongoing studies aim to identify mechanistic links between psychiatric or neurodegenerative diseases and the synaptic functions of axon guidance proteins.
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The authors declare no conflict of interest.
References
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Supported by grant 114965 to TEK from the Canadian Institutes of Health Research.
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Thompson-Steckel, G., Kennedy, T. Maintaining and Modifying Connections: Roles for Axon Guidance Cues in the Mature Nervous System. Neuropsychopharmacol 39, 246–247 (2014). https://doi.org/10.1038/npp.2013.212
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DOI: https://doi.org/10.1038/npp.2013.212