Neurocan Inhibits Semaphorin 3F Induced Dendritic Spine Remodeling Through NrCAM in Cortical Neurons

Abstract

Neurocan is a chondroitin sulfate proteoglycan present in perineuronal nets, which are associated with closure of the critical period of synaptic plasticity. During postnatal development of the neocortex dendritic spines on pyramidal neurons are initially overproduced; later they are pruned to achieve an appropriate balance of excitatory to inhibitory synapses. Little is understood about how spine pruning is terminated upon maturation. NrCAM (Neuron-glial related cell adhesion molecule) was found to mediate spine pruning as a subunit of the receptor complex for the repellent ligand Semaphorin 3F (Sema3F). As shown here in the postnatal mouse frontal and visual neocortex, Neurocan was localized at both light and electron microscopic level to the cell surface of cortical pyramidal neurons and was adjacent to neuronal processes and dendritic spines. Sema3F-induced spine elimination was inhibited by Neurocan in cortical neuron cultures. Neurocan also blocked Sema3F-induced morphological retraction in COS-7 cells, which was mediated through NrCAM and other subunits of the Sema3F holoreceptor, Neuropilin-2, and PlexinA3. Cell binding and ELISA assays demonstrated an association of Neurocan with NrCAM. Glycosaminoglycan chain interactions of Neurocan were required for inhibition of Sema3F-induced spine elimination, but the C-terminal sushi domain was dispensable. These results describe a novel mechanism wherein Neurocan inhibits NrCAM/Sema3F-induced spine elimination.

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

“…GWAS data show that NCAN is one of the common variants that are significantly associated with BPI risk [21,22,46,47]. NCAN is a proteoglycan that is involved in cell adhesion and neuronal migration, processes that are pivotal during neurodevelopment [42][43][44][45]84]. Our findings are relevant in the context of the hypotheses and previous evidence for the neurodevelopmental roots of the disease biology of BPI [13,85].…”

“…1b). NCAN is a proteoglycan that is a component of the neuronal extracellular matrix that is expressed during the modeling and remodeling of neuronal tissue and modulates neural adhesion and migration [42][43][44][45]. Genome-wide association studies have implicated common variation in NCAN as a risk for BPI [21,22,46,47].…”

Decreased Density of Perineuronal Net in Prelimbic Cortex Is Linked to Depressive-Like Behavior in Young-Aged Rats

“…Genetic studies in humans revealed that the variation of NCAN, a gene encoding PNN component protein neurocan, is a common risk factor for schizophrenia and bipolar disorder (Mühleisen et al, 2012;Oruč et al, 2012;Schultz et al, 2014). Neurocan has also been shown to regulate brain development, dendritic spine remodeling and the function of GABAergic interneurons (Zhou et al, 2001;Mohan et al, 2018;Sullivan et al, 2018). The assembly and function of PNNs are disrupted when these component proteins are hydrolyzed or the structures are destroyed, which could ultimately lead to negative consequences and pathophysiology of neuropsychiatric disorders (Wen et al, 2018;Testa et al, 2019).…”

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

“…During postnatal development, neurocan assembles around processes, dendritic spines, and soma of pyramidal neurons. Neurocan has been shown to inhibit Sema3F-mediated spine retraction in cortical neurons in culture by binding NrCAM and inhibiting its function within the Sema3F holoreceptor ( Figure 4B ; Mohan et al, 2018 ). Neurocan also binds to the Ig2 domain of NCAM at the EphA3 binding site, inhibiting the repellant response to EphrinA5 exhibited by remodeling basket cell terminals ( Sullivan et al, 2018 ).…”