The Postsynaptic Adenomatous Polyposis Coli (APC) Multiprotein Complex Is Required for Localizing Neuroligin and Neurexin to Neuronal Nicotinic Synapsesin Vivo

Abstract

Synaptic efficacy requires that presynaptic and postsynaptic specializations align precisely and mature coordinately. The underlying mechanisms are poorly understood, however. We propose that adenomatous polyposis coli protein (APC) is a key coordinator of presynaptic and postsynaptic maturation. APC organizes a multiprotein complex that directs nicotinic acetylcholine receptor (nAChR) localization at postsynaptic sites in avian ciliary ganglion neurons in vivo. We hypothesize that the APC complex also provides retrograde signals that direct presynaptic active zones to develop in register with postsynaptic nAChR clusters. In our model, the APC complex provides retrograde signals via postsynaptic neuroligin that interacts extracellularly with presynaptic neurexin. S-SCAM (synaptic cell adhesion molecule) and PSD-93 (postsynaptic density-93) are scaffold proteins that bind to neuroligin. We identify S-SCAM as a novel component of neuronal nicotinic synapses. We show that S-SCAM, PSD-93, neuroligin and neurexin are enriched at ␣3*-nAChR synapses. PSD-93 and S-SCAM bind to APC and its binding partner ␤-catenin, respectively. Blockade of selected APC and ␤-catenin interactions, in vivo, leads to decreased postsynaptic accumulation of S-SCAM, but not PSD-93. Importantly, neuroligin synaptic clusters are also decreased. On the presynaptic side, there are decreases in neurexin and active zone proteins. Further, presynaptic terminals are less mature structurally and functionally. We define a novel neural role for APC by showing that the postsynaptic APC multiprotein complex is required for anchoring neuroligin and neurexin at neuronal synapses in vivo. APC human gene mutations correlate with autism spectrum disorders, providing strong support for the importance of the association, demonstrated here, between APC, neuroligin and neurexin.

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

“…Mutations in ARX, FOXG1, and TSC1/2 are predicted to affect β-catenin/Wnt signaling levels and to cause changes in neuronal migration and maturation (Mak BC et al 2003; Seufert DW et al 2005; Danesin C et al 2009). MAGI-2/S-SCAM, a synaptic scaffold protein, binds directly to β-catenin and different S-SCAM isoforms are involved in both excitatory and inhibitory synapse assembly (Nishimura W et al 2002; Hirabayashi S et al 2004; Sumita K et al 2007; Rosenberg MM et al 2010). Lis1 binds directly to APC (Orlova KA and PB Crino 2010).…”

Neuroligin 2 Is Expressed in Synapses Established by Cholinergic Cells in the Mouse Brain

“…The synaptic scaffolding molecule (S-SCAM; [49]) is also present and interacts with NLGN2 at inhibitory synapses [50]. Furthermore, it was demonstrated that in chicken, where only three forms of NLGN is present (NLGN1,3,4) and NLGN2 is absent [51], S-SCAM is directly associated with NLGN1 at cholinergic synapses of the ciliary ganglion [52]. In these synapses, S-SCAM indirectly interacts with the adenomatous polyposis coli protein that organizes a multimolecular protein complex which targets α3 nicotinic ACh receptors to the postsynaptic membrane [53], [54].…”

MAGUKs, Synaptic Development, and Synaptic Plasticity

“…Recently, several MAGUKs were found to localize to neuronal nicotinic synapses with neuroligin 1 (NL1). S-SCAM, PSD-93, and PSD-95 are all enriched at synapses containing nicotinic acetylcholine receptors (nAChRs), and all 3 can bind to NL1; however, only S-SCAM influences the surface expression of NL1 (Rosenberg and others 2010). S-SCAM links NL1 to the postsynaptic adenomatous polyposis coli (APC) complex via β-catenin.…”

“…S-SCAM links NL1 to the postsynaptic adenomatous polyposis coli (APC) complex via β-catenin. NL1 binds to both the PDZ1 and WW domains of S-SCAM, and β-catenin associates with its PDZ5 domain (reviewed in Rosenberg and others 2010). The APC complex interacts with nAChRs, via the protein 14-3-3, and with cytoskeletal proteins.…”

“…Peptides that inhibit S-SCAM association with β-catenin and APC decrease the surface clustering of S-SCAM and NL1. Loss of NL1 also has a presynaptic effect; synaptic localization of its binding partner neurexin and associated active zone proteins is decreased, resulting in less mature terminals in avian ciliary ganglion neurons (Rosenberg and others 2010). Therefore, the S-SCAM/β-catenin/APC complex may serve to localize NL1 at nicotinic synapses and promote the maturation of presynaptic terminals.…”