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.
Highlights
Dendritic spines of cortical pyramidal neurons are the principal site of excitatory synapse formation
To determine if Neurocan was localized to cortical pyramidal neurons at adolescent (P18) and adult (P80) stages, immunofluorescence staining for Neurocan was performed in the medial frontal cortex (MFC) and primary visual cortex (V1)
We report here that Neurocan, one of the first chondroitin sulfate proteoglycans (CSPGs) to be expressed in the maturing neocortex (Carulli et al, 2010), is expressed coordinately with Semaphorin 3F (Sema3F) in postnatal and adult mouse brain in close apposition to dendritic spines and axon terminals
Summary
Dendritic spines of cortical pyramidal neurons are the principal site of excitatory synapse formation. Spines undergo dynamic changes during development, including rapid spinogenesis in early postnatal life, followed by substantial pruning during adolescence (Huttenlocher, 1979; McAllister, 2007; Petanjek et al, 2011; Bian et al, 2015). We showed that NrCAM, a neural cell adhesion molecule of the L1 family, regulates Semaphorin 3F (Sema3F)-mediated dendritic spine pruning in the mouse prefrontal and visual cortex during adolescence (Demyanenko et al, 2014; Mohan et al, 2018). NrCAM binds directly to Neuropilin-2 (Npn2), which associates with Plexin A3 (PlexA3) to form a Sema3F. In the presence of Sema3F, NrCAM promotes higher order clustering of Npn and PlexA3 on the neuronal membrane essential for spine pruning (Mohan et al, 2018)
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