Caldendrin Directly Couples Postsynaptic Calcium Signals to Actin Remodeling in Dendritic Spines

Abstract

Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling in dendritic spines. However, molecular mechanisms for the spatio-temporal regulation of filamentous actin (F-actin) dynamics by spinous Ca-transients are still poorly defined. We show that the postsynaptic Ca sensor caldendrin orchestrates nano-domain actin dynamics that are essential for actin remodeling in the early phase of long-term potentiation (LTP). Steep elevation in spinous [Ca] disrupts an intramolecular interaction of caldendrin and allows cortactin binding. The fast on and slow off rate of this interaction keeps cortactin in an active conformation, and protects F-actin at the spine base against cofilin-induced severing. Caldendrin gene knockout results in higher synaptic actin turnover, altered nanoscale organization of spinous F-actin, defects in structural spine plasticity, LTP, and hippocampus-dependent learning. Collectively, the data indicate that caldendrin-cortactin directly couple [Ca] to preserve a minimal F-actin pool that is required for actin remodeling in the early phase of LTP.

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

“…n = 17 dendritic segments of 12 cells in three independent cultures. E Representative kymograph from a DIV16 hippocampal neuron expressing PEX-GFP-KIF17 before and after LatA treatment (5 lM) (see also Fig EV4C-E spine synapses, the role and organization of the actin cytoskeleton at shaft synapses have not yet been addressed (Bosch et al, 2014;Konietzny et al, 2017;Mikhaylova et al, 2018). Using pharmacological approaches, we found that the actin mesh consisted of both branched and longitudinal filaments.…”

“…We found that the majority was spread over the dendritic shaft and is positive for excitatory but not inhibitory synaptic markers, and that their size correlates with the presence of homer1. In comparison with spine synapses, the role and organization of the actin cytoskeleton at shaft synapses have not yet been addressed (Bosch et al , ; Konietzny et al , ; Mikhaylova et al , ). Using pharmacological approaches, we found that the actin mesh consisted of both branched and longitudinal filaments.…”

“…Spinous F-actin is classified by filament type (branched or longitudinal) and functionally divided into a stable and dynamic pool. Actin dynamics are instrumental for activity-dependent structural plasticity of dendritic spines (Matsuzaki et al, 2004;Racz & Weinberg, 2013;Bosch et al, 2014;Kim et al, 2015;Mikhaylova et al, 2018). In addition to synapses located on spines, there is a smaller fraction of glutamatergic synapses formed directly on the dendritic shaft, but their contribution to neuronal function is investigated to a lesser extent (Bourne & Harris, 2011;Reilly et al, 2011).…”

Cytoskeletal makeup of the synapse: Shaft versus spine

“…Based on their turnover rate, actin filaments can be divided into dynamic and stable pools and based on the morphology described as linear or branched filaments. The controlled assembly and tread milling of F‐actin are essential for plasticity and stability of synapses (MacGillavry et al, ; Mikhaylova et al, ; Mundhenk, Fusi, & Kreutz, ; Stefen et al, ). Importantly, a plethora of actin nucleation factors, severing, and capping proteins are involved in filament formation and regulation of filament stability (Hotulainen & Hoogenraad, ).…”

“…In the proximity of the synaptic membrane, cortactin recruits the Arp2/3 complex via N‐WASP and promotes formation of new actin branches (Helgeson & Nolen, ). At the spine base, caldendrin keeps cortactin in an active conformation and protects F‐actin against cofilin‐induced severing (Mikhaylova et al, ). In line with these findings, the stable pool of spinous actin is no longer preserved in caldendrin deficient mice.…”