Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies

Figure 7

Shank3 and its interaction partners can affect actin cytoskeleton and spine morphology via various pathways. Shank3 and its many interaction partners can affect spine maturation and morphogenesis. Ankyrin repeat domain interaction partners, sharpin and α-fodrin, enable spine enhancement via Shank scaffold stabilization and F actin stabilization. SH3 domain interaction partner, Abp1, enhances F actin formation. Other scaffolding molecules, GKAP and Homer, can interact with Shank3 and take part in AMPA, NMDA, and mGluR modulation. Small GTPase modulator like βPIX activates Rac1 and/or Cdc42 and enables F actin formation and spine morphogenesis. Cortactin, intertion partner of proline-rich domain, binds and stabilizes F actin. Thus, most of the Shank3 interaction partners have a positive role in spine morphogenesis and mutations or deletions result in spine shrinkage and loss of synapses. An exception is Rich2. Rich2 deactivates Rac1 and/or Cdc42 and thus can take part in spine size reduction and spine loss. Shank3 bound Rich2 is inactive. Therefore, a switch between Shank3/Rich2 to Shank3 and unbound Rich2 at the PSD may be an important integrator of the translation of synaptic activity in controlled and restricted spine growth. It is mentionworthy that, at any certain time point, only one interaction partner of the same domain can bind with Shank3.