nArgBP2-SAPAP-SHANK, the core postsynaptic triad associated with psychiatric disorders

Abstract

Despite the complex genetic architecture, a broad spectrum of psychiatric disorders can still be caused by mutation(s) in the same gene. These disorders are interrelated with overlapping causative mechanisms including variations in the interaction among the risk-associated proteins that may give rise to the specific spectrum of each disorder. Additionally, multiple lines of evidence implicate an imbalance between excitatory and inhibitory neuronal activity (E/I imbalance) as the shared key etiology. Thus, understanding the molecular mechanisms underlying E/I imbalance provides essential insight into the etiology of these disorders. One important class of candidate risk genes is the postsynaptic scaffolding proteins, such as nArgBP2, SAPAP, and SHANK that regulate the actin cytoskeleton in dendritic spines of excitatory synapses. This review will cover and discuss recent studies that examined how these proteins, especially nArgBP2, are associated with psychiatric disorders. Next, we propose a possibility that variations in the interaction among these proteins in a specific brain region might contribute to the onset of diverse phenotypes of psychiatric disorders.

Fig. 1. The domain architectures of nArgBP2, SHANK, and SAPAP.

Proteins listed with each of the domains indicate the known binding partners. Only a subset of known interacting proteins is shown. nArgBP2, SHANK, and SAPAP interact with each other either directly via specific domains (red lines) or indirectly through common binding partners (broken lines). SAPAP interacts with nArgBP2 via its proline-rich region between the DLC and GH1 regions. 14 aa 14 amino acid domain, Abi Abelson interacting protein-1, DLC dynein light chain, GH1 GKAP homology 1, nArgBP2 neural Arg binding protein 2, PDZ PSD95 Dlg1 and zo-, 1 PSD95 postsynaptic density protein 95, SAM sterile alpha motif, SAPAP SAP90/PSD95-associated protein, SHANK SH3 and multiple ankyrin repeat domains, SH3 Src homology 3 domain, SoHo sorbin homology domain, S-SCAM synaptic scaffolding molecule, WAVE WASP (Wiskott–Aldrich syndrome protein)-family verprolin homologous protein

Fig. 2. Schematic description of the role of nArgBP2 in excitatory spine-synapse formation and maintenance of E/I balance.

In the normal condition, nArgBP2 plays a role in controlling actin cytoskeleton dynamics through the WAVE and PAK/cofilin cascade. Its ablation, however, increases actin dynamics via uncontrolled phosphorylation of the WAVE/PAK/cofilin pathway, causing a robust and selective inhibition of excitatory spine-synapse formation. This subsequently leads to an excitatory/inhibitory synaptic imbalance. Since the excitatory/inhibitory synaptic imbalance likely leads to a broad spectrum of psychiatric disorders, nArgBP2 KD, which selectively alters excitatory synapse formation, may account for the manic/bipolar-like behaviors observed in nArgBP2 KO mice

Fig. 3. Hypothetical model proposing the postsynaptic triad of nArgBP2-SAPAP-SHANK as a convergent pathway of psychiatric disorders.

nArgBP2, SAPAP, and SHANK interact with each other, forming a structural and functional postsynaptic scaffold. They also organize multiple interactomes to regulate the actin cytoskeleton. Alterations in the expression of either one or more of the proteins participating in the core triad would break the interactome balance and induce actin cytoskeleton dysregulation, leading to abnormal spine formation and morphogenesis, which consequently undermines excitatory synapse formation. Depending on levels of expression or activity of this core triad in a specific brain region, diverse levels of E/I imbalance may lead to the numerous phenotypes of psychiatric disorders. Thus, actin regulation by the core triad in dendritic spines is a convergent mechanism for various psychiatric disorders such as ASD, BD, OCD, and SCZ