SynDIG1: An Activity-Regulated, AMPA- Receptor-Interacting Transmembrane Protein that Regulates Excitatory Synapse Development

Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
Neuron (Impact Factor: 15.05). 01/2010; 65(1):80-93. DOI: 10.1016/j.neuron.2009.12.021
Source: PubMed


During development of the central nervous system, precise synaptic connections between presynaptic and postsynaptic neurons are formed. While significant progress has been made in our understanding of AMPA receptor trafficking during synaptic plasticity, less is known about the molecules that recruit AMPA receptors to nascent synapses during synaptogenesis. Here we identify a type II transmembrane protein (SynDIG1) that regulates AMPA receptor content at developing synapses in dissociated rat hippocampal neurons. SynDIG1 colocalizes with AMPA receptors at synapses and at extrasynaptic sites and associates with AMPA receptors in heterologous cells and brain. Altered levels of SynDIG1 in cultured neurons result in striking changes in excitatory synapse number and function. SynDIG1-mediated synapse development is dependent on association with AMPA receptors via its extracellular C terminus. Intriguingly, SynDIG1 content in dendritic spines is regulated by neuronal activity. Altogether, we define SynDIG1 as an activity-regulated transmembrane protein that regulates excitatory synapse development.

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    • "For example, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate glutamate receptors, which mediate excitatory synaptic transmission, were upregulated in AGRP neurons (Gria3: +3.4-fold, q = 2e −5 , Grik1: +3.0-fold, q = 0.03; Grik3: +3.2-fold, q = 0.005), but not in POMC neurons (see Ion Channels, below). Food-deprivation also induced upregulation of excitatory synaptogenic genes in AGRP neurons (Syndig1: +8.3-fold, q = 0.008; Syndig1l: +13.2-fold, q = 0.0001) (Kalashnikova et al., 2010; Lovero et al., 2013) as well as kinases (Figure 1—figure supplement 2C) that regulate activitydependent changes in spine morphology and excitatory synaptic plasticity, such as p21-associated kinase 3 (Pak3, +2.0-fold, q = 4e −7 ), "
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    • "These mechanisms have by and large been confirmed in slice cultures and in vivo (Fischer et al., 1998; Dunaevsky et al., 1999; Majewska and Sur, 2003). One approach that has been instrumental in the discovery of synaptogenic adhesion complexes is the use of co-cultures of neurons and heterologous cells (Scheiffele et al., 2000; Biederer et al., 2002; Graf et al., 2004; Kayser et al., 2006; Kim et al., 2006; Linhoff et al., 2009; Kalashnikova et al., 2010). In these mixed cultures, candidate synaptogenic proteins are expressed in heterologous cells and their ability to induce synaptogenesis in contacting neurons is assessed by immunostaining of synaptic markers (Biederer and Scheiffele, 2007). "
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