CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation

Abstract

Ca 2+ /calmodulin-dependent kinase IIα (CaMKIIα) is essential for synaptic plasticity and learning by decoding synaptic Ca 2+ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKIIα's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKIIα. We demonstrate that Shank3 and GluN2B, via combined actions of Ca 2+ and phosphatases, reciprocally bind to CaMKIIα. Under basal condition, CaMKIIα is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca 2+ concentration induces GluN2Bmediated recruitment of active CaMKIIα and formation of the CaMKIIα/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca 2+ removal. Protein phosphatases control the Ca 2+ -dependent shuttling of CaMKIIα between the two PSD subcompartments and PSD condensate formation. Activation of CaMKIIα further enlarges the PSD assembly and induces structural LTP. Thus, Ca 2+ -induced and phosphatase-checked shuttling of CaMKIIα between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.

Synaptic protein interaction networks encode experience by assuming stimulus-specific and brain-region-specific states

“…Far from a static “scaffold,” the post-synaptic density is a dynamic, liquid-liquid-phase-separated ( Cai et al, 2021 ; Feng et al, 2019 ; Zeng et al, 2016 , 2018 ) structure that rapidly responds to synaptic activity by altering its molecular composition via regulation of protein-protein interactions. Certainly, individual interactions, such as recruitment of AMPARs to PSD95 scaffolds ( Buonarati et al, 2019 ; Ehrlich and Malinow, 2004 ) or dissociation of mGluR from Homer EVH1 domains ( Guo et al, 2015 ; Ronesi et al, 2012 ) are well-characterized, but the molecular logic that allows a change in protein interactions to translate into functional cellular “calculations” ( Figure 1A ) remains understudied, partly due to technical limitations.…”

Synaptic signaling networks encode experience by assuming stimulus-specific and brain-region-specific states

“…Far from a static 'scaffold', the postsynaptic density is a dynamic, liquid-liquidphase-separated [53][54][55][56] structure that rapidly responds to incoming synaptic activity by altering its molecular composition via regulation of protein-protein interactions. Certainly, individual interactions, such as recruitment of AMPARs to PSD95 scaffolds [57,58] or dissociation of mGluR from Homer EVH1 domains [33,34] are well-characterized, but the molecular logic that allows a change in protein interactions to translate into functional cellular 'calculations' (Fig 1A) remains understudied, partly due to technical limitations.…”

The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models

“…Additionally, CaMKIIα plays an essential role in the regulation of memory and learning processes, as well as an activity-dependent role in spine density limitation during postnatal development [42,43]. One recent study found that CaMKIIα is recruited to the scaffolding protein SHANK3 sub-compartment of the PSD [44]. Moreover, the binding of SHANK3 to CaMKIIα potentially modulates dendritic spine morphology [45].…”