Coordination of Synaptic Adhesion with Dendritic Spine Remodeling by AF-6 and Kalirin-7

Abstract

Remodeling of central excitatory synapses is crucial for synapse maturation and plasticity, and contributes to neurodevelopmental and psychiatric disorders. Remodeling of dendritic spines and the associated synapses has been postulated to require the coordination of adhesion with spine morphology and stability; however, the molecular mechanisms that functionally link adhesion molecules with regulators of dendritic spine morphology are mostly unknown. Here, we report that spine size and N-cadherin content are tightly coordinated. In rat mature cortical pyramidal neurons, N-cadherin-dependent adhesion modulates the morphology of existing spines by recruiting the Rac1 guanine-nucleotide exchange factor kalirin-7 to synapses through the scaffolding protein AF-6/afadin. In pyramidal neurons, N-cadherin, AF-6, and kalirin-7 colocalize at synapses and participate in the same multiprotein complexes. N-cadherin clustering promotes the reciprocal interaction and recruitment of N-cadherin, AF-6, and kalirin-7, increasing the content of Rac1 and in spines and PAK (p21-activated kinase) phosphorylation. N-cadherin-dependent spine enlargement requires AF-6 and kalirin-7 function. Conversely, disruption of N-cadherin leads to thin, long spines, with reduced Rac1 contact, caused by uncoupling of N-cadherin, AF-6, and kalirin-7 from each other. By dynamically linking N-cadherin with a regulator of spine plasticity, this pathway allows synaptic adhesion molecules to rapidly coordinate spine remodeling associated with synapse maturation and plasticity. This study hence identifies a novel mechanism whereby cadherins, a major class of synaptic adhesion molecules, signal to the actin cytoskeleton to control the morphology of dendritic spines, and outlines a mechanism that underlies the coordination of synaptic adhesion with spine morphology.

Rapid modulation of spine morphology by the 5-HT 2A serotonin receptor through kalirin-7 signaling

“…PAK is a molecular target of activated Rac, and is an important regulator of the actin cytoskeletal rearrangements that underlie spine remodeling. Activation of a Rac/PAK pathway induces larger spines (20)(21)(22); thus, we hypothesized that activation of 5-HT 2A receptors influences PAK signaling. We incubated cultured cortical neurons with DOI and examined phosphorylation of PAK on residue T423; phosphorylation at this site is indicative of activation by GTP-bound Rac1 or Cdc42 (31).…”

“…Kalirin-7 is enriched in the postsynaptic density of excitatory synapses in the mammalian forebrain, and its activation enhances Rac activation, p21-activated kinase (PAK) phosphorylation, dendritic spine maintenance and morphogenesis, and AMPA receptor trafficking (19)(20)(21). Kalirin-7 interacts with several synaptic protein complexes in neurons, including complexes associated with EphB receptors (21), NMDA receptors (20), and N-cadherin (22). The PDZ-binding motif located on the C terminus of kalirin-7 mediates its interaction with PSD-95 (20), and may allow it to interact with other PDZdomain-containing proteins (19).…”

Synaptic Localization and Activity of ADAM10 Regulate Excitatory Synapses through N-Cadherin Cleavage

“…Since N-cadherin signaling leads to modulation of spine morphology and synapse stability (Abe et al, 2004;Xie et al, 2008;Mendez et al, 2010), we asked whether the increased synaptic accumulation of N-cadherin FL, as obtained by TAT-Pro treatment, could be paralleled by modifications of spine morphology.…”

“…ADAM10 localization and activity influence subunit composition of synaptic AMPA receptors N-Cadherin regulates the number of AMPA receptors at synapses (Liao et al, 1999;Togashi et al, 2002;Kasai et al, 2003) and can interact with specific subunits of AMPA receptors (Dunah et al, 2005;Nuriya and Huganir, 2006;Saglietti et al, 2007). More recently, it has been shown that N-cadherin inactivation results in fewer GluR1 synaptic clusters (Xie et al, 2008).…”

“…Moreover, at synapses, N-cadherin regulates synaptic adhesion, spine morphology, and activity-dependent plasticity (Togashi et al, 2002;Okamura et al, 2004;Xie et al, 2008;Mendez et al, 2010). Recent studies also showed that N-cadherin is mandatory for an increase in AMPA receptor content and function at synaptic sites (Liao et al, 1999;Okuda et al, 2007;Saglietti et al, 2007;Tai et al, 2008;Xie et al, 2008), which is associated with spine enlargement (Kasai et al, 2003;Abe et al, 2004;Mendez et al, 2010). Thus, a temporal and functional relationship between N-cadherin, synaptic accumulation of AMPA receptors, and spine growth has been put forward (Zito et al, 2009).…”