Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies

Abstract

Shank proteins (Shank1, Shank2, and Shank3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular SHANK2 and SHANK3, lead to autism spectrum disorders (ASD) in both human and mouse models. Shank3 proteins are made of several domains—the Shank/ProSAP N-terminal (SPN) domain, ankyrin repeats, SH3 domain, PDZ domain, a proline-rich region, and the sterile alpha motif (SAM) domain. Via various binding partners of these domains, Shank3 is able to bind and interact with a wide range of proteins including modulators of small GTPases such as RICH2, a RhoGAP protein, and βPIX, a RhoGEF protein for Rac1 and Cdc42, actin binding proteins and actin modulators. Dysregulation of all isoforms of Shank proteins, but especially Shank3, leads to alterations in spine morphogenesis, shape, and activity of the synapse via altering actin dynamics. Therefore, here, we highlight the role of Shank proteins as modulators of small GTPases and, ultimately, actin dynamics, as found in multiple in vitro and in vivo models. The failure to mediate this regulatory role might present a shared mechanism in the pathophysiology of autism-associated mutations, which leads to dysregulation of spine morphogenesis and synaptic signaling.

TRAF6 controls spinogenesis instructing synapse density and neuronal activity through binding neuroplastin

“…Additionally, this finding matches with previous observations, i.e. a tight correlation between the fast up-regulation of expression of neuroplastin and intracellular synaptic proteins during early synaptogenesis in cultured and in acutely isolated rat hippocampal slices(Buckby et al, 2004) as well as the stabilization and maturation of spines(Böckers et al, 1999;Sarowar and Grabrucker 2016).…”

“…To characterize the nature of neuroplastin-promoted dendritic protrusions, we evaluated the appearance of Shank2, a well-established early marker (Grabrucker et al, 2011;Sarowar and Grabrucker 2016) and key organizer (Roussignol et al, 2005) of functional postsynapses. While transfection of Np65-GFP at 7DIV increased dendritic protrusion density compared to transfection with control GFP, the relative abundance of Shank2-positive vs. Shank2-negative protrusions (Protrusion fraction) was not different between Np65-GFP-tranfected and GFP-transfected rat neurons at 9 DIV ( Figure 1F,H).…”

Shank3B mutant mice display pitch discrimination enhancements and learning deficits

“…Previous studies have established a decrease in NMDAR‐mediated hippocampal LTP in Shank3 KOs (Bozdagi et al, 2010; Wang et al, 2011; Yang et al, 2012; Kouser et al, 2013; Jaramillo et al, 2017). Shank3 is also involved in controlling actin dynamics and glutamate receptor‐mediated synaptic transmission and plasticity (Peça et al, 2011; Verpelli et al, 2011; Durand et al, 2012; Duffney et al, 2013; Chana et al, 2015; Sarowar and Grabrucker, 2016). These mechanistic features are most likely driving learning deficits.…”

The regulation of glycogenolysis in the brain

“…Rac1 activation through Wnt5a signaling in brain influences synaptic plasticity and memory formation (79), and through its binding and activation of GP it may potentially couple actin dynamics and glycogenolysis, both linked to memory consolidation (80). Furthermore, as a modulator of actin dynamics (81), Rac1 also plays an important role in neuronal migration and synaptic plasticity (79,82,83).…”