title: PSD93 regulates synaptic stability at neuronal cholinergic synapses.
abstract: Neuronal cholinergic synapses play important roles in both the PNS and CNS. However, the mechanisms that regulate the formation, maturation, and stability of neuronal cholinergic synapses are poorly understood. In this study, we use the readily accessible mouse superior cervical ganglion (SCG) and submandibular ganglion (SMG) to examine the assembly of the postsynaptic complex of neuronal cholinergic synapses. We find that novel splicing forms of PSD93 (postsynaptic density 93) are expressed in SCG. By immunostaining, we show that PSD93 proteins precisely colocalize with neuronal nicotinic acetylcholine receptors (nAChRs) at synapses of the SCG and SMG. Subcellular fractionation demonstrates that PSD93 is enriched in the PSD fraction of SCG, and coimmunoprecipitation shows that PSD93 and neuronal nAChRs form a complex in vivo. Furthermore, two additional components of the well characterized glutamatergic postsynaptic complex, GKAP/SAPAP (guanylate kinase domain-associated protein/synapse-associated protein-associated protein) and Shank/ProSAP family proteins, are also present at neuronal cholinergic synapses. To assess the function of this protein complex at neuronal cholinergic synapses in vivo, we examined ganglia in mice that lack PSD93. We find that neuronal cholinergic synapses form properly in PSD93 null mice. After denervation, however, synaptic clusters of nAChRs disassemble much faster in mice lacking PSD93 than those in wild-type mice. These results demonstrate that PSD93 is a key component of the postsynaptic scaffold at neuronal cholinergic synapses and plays an important role in synaptic stability. In addition, these results suggest that the mechanism of postsynaptic scaffolding is conserved between neuronal cholinergic and glutamatergic synapses.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.forename: Shengli
authors.initials: S
authors.lastname: Zhao
authors.forename: David S
authors.initials: DS
authors.lastname: Bredt
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011950:Receptors, Cholinergic / Q000032:analysis* / Q000378:metabolism; D016415:Sequence Alignment; D013569:Synapses / Q000737:chemistry* / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D011950:Receptors, Cholinergic; C033652:postsynaptic density proteins