Developmental regulation of GABAergic interneuron branching and synaptic development in the prefrontal cortex by soluble neural cell adhesion molecule

Abstract

Neural cell adhesion molecule, NCAM, is an important regulator of neuronal process outgrowth and synaptic plasticity. Transgenic mice that overexpress the soluble NCAM extracellular domain (NCAM-EC) have reduced GABAergic inhibitory and excitatory synapses, and altered behavioral phenotypes. Here, we examined the role of dysregulated NCAM shedding, modeled by overexpression of NCAM-EC, on development of GABAergic basket interneurons in the prefrontal cortex. NCAM-EC overexpression disrupted arborization of basket cells during the major period of axon/dendrite growth, resulting in decreased numbers of GAD65- and synaptophysin-positive perisomatic synapses. NCAM-EC transgenic protein interfered with interneuron branching during early postnatal stages when endogenous polysialylated (PSA) NCAM was converted to non-PSA isoforms. In cortical neuron cultures, soluble NCAM-EC acted as a dominant inhibitor of NCAM-dependent neurite branching and outgrowth. These findings suggested that excess soluble NCAM-EC reduces perisomatic innervation of cortical neurons by perturbing axonal/dendritic branching during cortical development.

The Neural Cell Adhesion Molecule Promotes FGFR-Dependent Phosphorylation and Membrane Targeting of the Exocyst Complex to Induce Exocytosis in Growth Cones

“…In agreement, NCAM-deficient mice show abnormalities in axonal growth and fasciculation in the hippocampus (Cremer et al, 1997;Seki and Rutishauser, 1998). Furthermore, inhibition of the homophilic interactions of NCAM by the secreted extracellular domain of NCAM results in impaired development of GABAergic basket interneurons in the prefrontal cortex (Brennaman and Maness, 2008), indicating that NCAM plays an important role in regulation of neurite outgrowth and neuronal development in vivo. Previously, changes in cytoskeleton dynamics and gene expression were considered to be the major mechanisms by which NCAM influences neurite outgrowth.…”

A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex

“…Notably, changes in basket cells have been found in other mouse models with altered polySia or NCAM levels. Transgenic mice overexpressing the extracellular domain of NCAM show reduced perisomatic innervation from basket cells and impaired synaptic plasticity in the PFC (Pillai-Nair et al, 2005;Brennaman and Maness, 2008;Brennaman et al, 2011). Premature removal of polySia induced untimely maturation of perisomatic innervation and the onset of critical period plasticity in the visual cortex (Di Cristo et al, 2007).…”

The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-associated protein kinase (ROCK)-mediated Growth Cone Collapse

“…Dissociated cortical neurons from NCAM KO mice (E15.5) were plated onto poly-D-lysine-and laminin-coated Lab-Tek II chamber slides (1.5 ϫ 10 5 cells/well) as described previously (74,76). At 10 DIV, NCAM KO neurons were co-transfected with WT or mutant NCAM140 and pCAG-IRES-EGFP using Lipofectamine 2000, and 48 h later, cells were stimulated with 1 g/ml preclustered Fc or ephrin-A5-Fc for 30 min.…”