Interfering with Semaphorin3A in perineuronal nets to enhance plasticity

Authors: D. CARULLI, R. BROERSEN, F. DE WINTER, H.-J. BOELE, B. HOBO, C. CANTO, E. M. MUIR, C. I. DE ZEEUW, J. VERHAAGEN

Daniela Carulli, visiting Professor with Verhaagen Lab Group

Lab Abstract:
Neuronal plasticity is crucial for our brain to learn, adapt to the environment and recover from brain injury. Plasticity decreases with age, particularly after childhood/adolescence. Perineuronal nets (PNNs) play a crucial role in restricting plasticity in the adult central nervous system. However, it is not entirely known how they act. PNNs are macromolecular assemblies of extracellular matrix and are composed of hyaluronan and chondroitin sulfate proteoglycans, which are kept together by link proteins and tenascin-R. We recently identified the chemorepulsive axon guidance protein Semaphorin3A (Sema3A) as a prominent component of PNN, suggesting that it may be a prime candidate in the control of PNN-mediated plasticity. To test this hypothesis we investigated the effect of interfering with Sema3A in the PNN of the deep cerebellar nuclei (DCN) of adult mice, at both the synaptic and behavioral level. Given that the DCN have abundant PNNs and are essential for associative eyeblink conditioning, they form a brain structure that is uniquely suited to investigate the role of PNN-associated Sema3A in learning-associated plasticity. To interfere with Sema3A signaling, we used an adeno-associated viral vector (AAV) encoding a soluble form of the Sema3A receptor component Neuropilin-1 (NP1-Y297A-Fc). NP1-Y297A-Fc retains its ability to interact with Sema3A, while binding with its other ligand, vascular endothelial growth factor (VEGF), is abolished by the mutation Y297A. With this approach, NP1-Y297A-Fc would act locally as a scavenger for Sema3A in the nets. We found that treatment with NP1-Y297A-Fc induces a significant increase in the size of axon terminals of Purkinje cells (the main inhibitory input on DCN neurons), which retain their discrete distribution along the target neuron membrane. In contrast, the digestion of the whole PNNs by the enzyme chondroitinase results in a decreased partition between neighboring Purkinje terminals. During associative motor learning, i.e. in mice subjected to eyeblink conditioning, PNNs and their Sema3A content in the DCN are reduced, suggesting that Sema3A plays an inhibitory role in the formation of this type of memory. Notably, digesting the whole PNNs in the DCN leads to faster learning in the eyeblink conditioning paradigm. These data show that PNNs are crucial for cerebellar plasticity and cerebellum-dependent learning, and support the hypothesis that the chemorepulsive axon guidance cue Sema3A is an effector protein with a key role in PNN-mediated plasticity.

Abstract Citation
D. CARULLI1,3, R. BROERSEN2,4, *F. DE WINTER1, H.-J. BOELE4, B. HOBO1, C. CANTO2,4, E. M. MUIR5, C. I. DE ZEEUW2,4, J. VERHAAGEN1;
1Lab. for Neuroregeneration, 2Lab. for Cerebellar Coordination and Cognition, Netherlands Inst. for Neurosci., Amsterdam, Netherlands; 3Dept. of Neurosci. and Neurosci. Inst. Cavalieri-Ottolenghi, Univ. of Turin, Turin, Italy; 4Dept. of Neurosci., Erasmus MC, Rotterdam, Netherlands; 5Dept. of Physiology, Develop. and Neurosci., Univ. of Cambridge, Cambridge, United Kingdom. Interfering with Semaphorin3A in perineuronal nets to enhance plasticity. Program No. 201.13. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

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