Cortactin Contributes to Activity-Dependent Modulation of Spine Actin Dynamics and Spatial Memory Formation

Abstract

Postsynaptic structures on excitatory neurons, dendritic spines, are actin-rich. It is well known that actin-binding proteins regulate actin dynamics and by this means orchestrate structural plasticity during the development of the brain, as well as synaptic plasticity mediating learning and memory processes. The actin-binding protein cortactin is localized to pre- and postsynaptic structures and translocates in a stimulus-dependent manner between spines and the dendritic compartment, thereby indicating a crucial role for synaptic plasticity and neuronal function. While it is known that cortactin directly binds F-actin, the Arp2/3 complex important for actin nucleation and branching as well as other factors involved in synaptic plasticity processes, its precise role in modulating actin remodeling in neurons needs to be deciphered. In this study, we characterized the general neuronal function of cortactin in knockout mice. Interestingly, we found that the loss of cortactin leads to deficits in hippocampus-dependent spatial memory formation. This impairment is correlated with a prominent dysregulation of functional and structural plasticity. Additional evidence shows impaired long-term potentiation in cortactin knockout mice together with a complete absence of structural spine plasticity. These phenotypes might at least in part be explained by alterations in the activity-dependent modulation of synaptic actin in cortactin-deficient neurons.

The Alzheimer’s disease risk gene CD2AP functions in dendritic spines by remodelling F-actin

“…The CD2AP-cortactin interaction contributes to F-actin stabilisation and accumulation in vivo (Wang & Brieher, 2020). Cortactin knockdown reduces spine density (Catarino et al, 2013; Cornelius et al, 2021; Hering & Sheng, 2003), similar to CD2AP knockdown. Cortactin stabilizes the ARP2/3 dependent branched F-actin, delays its depolymerisation, and can directly activate the ARP2/3 complex (Weaver et al, 2001), supporting a similar role for CD2AP.…”

“…CD2AP could act through its interaction partners, cortactin and capping protein (CP), which have known functions in spines via spinal F-actin regulation (Catarino et al, 2013; Cornelius et al, 2021; Fan et al, 2011; Hering & Sheng, 2003). The CD2AP-cortactin interaction contributes to F-actin stabilisation and accumulation in vivo (Wang & Brieher, 2020).…”

Multiplex imaging of human induced pluripotent stem cell-derived neurons with CO-Detection by indEXing (CODEX) technology

“…By contrast, the vesicular transmembrane protein SYP is a synaptic marker that appears later during development, where it is involved in the activity-dependent synapse formation and trafficking of synaptic vesicles to presynaptic terminals (White and Stowell, 2021). We also included markers for proteins important in neuronal development to further verify the neuronal identity of our iPSC-derived neurons, including the calcium/calmodulin-dependent protein kinase II (CAMK2 Figure 3B) (Kool et al, 2019; Wang et al, 2013), the actin-binding protein cortactin (CTTN, Figure 3B) (Cornelius et al, 2021), and the microtubule-associated protein doublecortin (DCX, Figure 4B) (Ayanlaja et al, 2017).…”

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation

“…It is reported that SYT1 expression is reduced in Alzheimer’s disease brains as a result of synaptic loss [83] . Cortactin, localized in pre- and post-synaptic structures, recently when studied in knockout mice showed deficits in hippocampus-dependent spatial memory formation with impaired long-term potentiation and complete loss of structural spine plasticity [84] . Noteworthy, another study discusses the implications of mutations in Parkin, a ubiquitin ligase, causing Parkinson’s disease.…”