SALM Synaptic Cell Adhesion-like Molecules Regulate the Differentiation of Excitatory Synapses

Abstract

Synaptic cell adhesion molecules (CAMs) are known to play key roles in various aspects of synaptic structures and functions, including early differentiation, maintenance, and plasticity. We herein report the identification of a family of cell adhesion-like molecules termed SALM that interacts with the abundant postsynaptic density (PSD) protein PSD-95. SALM2, a SALM isoform, distributes to excitatory, but not inhibitory, synaptic sites. Overexpression of SALM2 increases the number of excitatory synapses and dendritic spines. Mislocalized expression of SALM2 disrupts excitatory synapses and dendritic spines. Bead-induced direct aggregation of SALM2 results in coclustering of PSD-95 and other postsynaptic proteins, including GKAP and AMPA receptors. Knockdown of SALM2 by RNA interference reduces the number of excitatory synapses and dendritic spines and the frequency, but not amplitude, of miniature excitatory postsynaptic currents. These results suggest that SALM2 is an important regulator of the differentiation of excitatory synapses.

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

“…Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11)(12)(13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail.…”

“…All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11)(12)(13). SALMs are expressed early in the developing nervous system and persist into adulthood.…”

“…SALM1 also enhances the surface expression of N-methyl-D-asparatate receptors, and this may involve either a direct SALM/N-methyl-D-asparatate receptor interaction or an indirect interaction through a PDZ protein (11). Overexpression of SALM2 increases the number of excitatory synapses and dendritic spines, whereas knock-down of SALM2 decreases the number of excitatory synapses and spines (12). Thus, SALMs, like other adhesion molecules, have multiple functions in the nervous system.…”

“…The Myc-SALM1⌬4 and Myc-SALM2⌬7 constructs were also generated using QuikChange mutagenesis by inserting a stop codon before the PDZ-binding motif, resulting in a 4-amino acid truncation of SALM1 and 7-amino acid deletion of SALM2. SALM5 pGW1 was a gift from Dr. Eunjoon Kim (KAIST, Korea) (12).…”

The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

“…Among the factors that regulate the development of neural circuits, proteins containing extracellular leucine-rich repeat (LRR) domains have recently emerged as key organizers of connectivity (de Wit et al, 2011;Ko and Kim, 2007). Artificial synapse formation assays have shown that a host of LRR-containing proteins, which are widely and highly expressed in the brain, are capable of recruiting various synaptic scaffolds and inducing synaptic differentiation in heterologous cells in which these LRR-containing proteins are exogenously expressed (de Wit et al, 2009;Kim et al, 2006;Ko et al, 2006;Linhoff et al, 2009;Mah et al, 2010;Takahashi et al, 2011;Woo et al, 2009). Selected LRR proteins that function at synapses are shown in Fig.…”