Abstract
Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.
Highlights
IntroductionThe mouse medial frontal cortex (referred to as PFC hereafter), is considered to share overlapping functional homology with human prefrontal cortex, including regulation of working memory and social function[14]
The mouse medial frontal cortex, is considered to share overlapping functional homology with human prefrontal cortex, including regulation of working memory and social function[14]
Ephrin-A repellent ligands in the mouse PFC engage a receptor complex consisting of the tyrosine kinase EphA3 and immunoglobulin (Ig)-class cell adhesion molecule NCAM, which signals within GABAergic axon terminals to constrain the density of basket cell synapses at the perisomatic region of pyramidal cells[15,16]
Summary
The mouse medial frontal cortex (referred to as PFC hereafter), is considered to share overlapping functional homology with human prefrontal cortex, including regulation of working memory and social function[14]. Deletion of NCAM, EphA3, or ephrin-A2,-A3,-A5 in mice increases the density of perisomatic basket cell synapses[16], consistent with a role for NCAM and EphA3 in ephrin-A-induced synaptic remodeling. To investigate a role for neurocan as a regulator of ephrinA5-induced perisomatic synapse remodeling, we investigated its ability to perturb the functional interactions of NCAM and EphA3 in the developing mouse PFC. To determine if neurocan regulates ephrinA5-induced perisomatic synapse remodeling, we investigated its ability to perturb the functional interactions of NCAM and EphA3 in the developing mouse PFC. Neurocan inhibited ephrinA5-induced clustering of NCAM and EphA3, impairing EphA3 kinase activation and GABAergic axon repulsion These results delineate a novel mechanism by which neurocan-containing PNNs terminate postnatal remodeling of basket cell terminals by inhibiting the interaction of NCAM with EphA3 in the PFC
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