Abstract
Homer1 is a synaptic scaffold protein that regulates glutamatergic synapses and spine morphogenesis. HOMER1 knockout (KO) mice show behavioral abnormalities related to psychiatric disorders, and HOMER1 has been associated with psychiatric disorders such as addiction, autism disorder (ASD), schizophrenia (SZ), and depression. However, the mechanisms by which it promotes spine stability and its global function in maintaining the synaptic proteome has not yet been fully investigated. Here, we used computational approaches to identify global functions for proteins containing the Homer1-interacting PPXXF motif within the postsynaptic compartment. Ankyrin-G was one of the most topologically important nodes in the postsynaptic peripheral membrane subnetwork, and we show that one of the PPXXF motifs, present in the postsynaptically-enriched 190 kDa isoform of ankyrin-G (ankyrin-G 190), is recognized by the EVH1 domain of Homer1. We use proximity ligation combined with super-resolution microscopy to map the interaction of ankyrin-G and Homer1 to distinct nanodomains within the spine head and correlate them with spine head size. This interaction motif is critical for ankyrin-G 190’s ability to increase spine head size, and for the maintenance of a stable ankyrin-G pool in spines. Intriguingly, lack of Homer1 significantly upregulated the abundance of ankyrin-G, but downregulated Shank3 in cortical crude plasma membrane fractions. In addition, proteomic analysis of the cortex in HOMER1 KO and wild-type (WT) mice revealed a global reshaping of the postsynaptic proteome, surprisingly characterized by extensive upregulation of synaptic proteins. Taken together, we show that Homer1 and its protein interaction motif have broad global functions within synaptic protein-protein interaction networks. Enrichment of disease risk factors within these networks has important implications for neurodevelopmental disorders including bipolar disorder, ASD, and SZ.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.The structural plasticity of dendritic spines is governed by several processes including spine formation, maturation, stabilization, remodeling, and elimination
To determine whether Homer1binding proteins are enriched in the postsynaptic density (PSD), we retrieved all PPXXF-containing proteins identified in UniProt (n = 1995) with the aid of the MOTIF search and performed a gene set analysis with genes encoded by PSD proteins [35, 36]
We found a significant enrichment of PPXXF motifcontaining proteins in genome-wide significant loci from bipolar disorder (BD) genome-wide association studies (GWAS) (7/120) and de novo variants associated with autism spectrum disorder (ASD) and SZ (30/1167)
Summary
Changes in spine number and morphology, along with the glutamate receptor content of synapses, contribute to functional connectivity in synaptic circuits [1]. Altered spine density in cortical pyramidal neurons has been observed in postmortem studies of patients with schizophrenia (SZ), bipolar disorder (BD), autism spectrum disorder (ASD), and intellectual disability (ID) [2,3,4,5]. Dendritic spine abnormalities on cortical pyramidal neurons have emerged as key cellular substrates in the pathogenesis of several psychiatric disorders [6, 7]. The Homer family consists of three members in mammals, Homer, Homer, and Homer, all of which are postsynaptic density scaffolding proteins highly expressed in the central nervous system. Homer protein regulates glutamatergic synapses and spine morphogenesis [8,9,10]
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