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.
Highlights
Activity-dependent plasticity is associated with functional as well as structural changes at synapses and plays a vital role both during development and for cognitive functions as, for instance, processes of learning and memory formation [1,2,3]
The main underlying force needed for structural changes at synapses as well as for alterations in the composition of surface receptors in response to external stimuli is generated by the actin cytoskeleton, via actin-binding proteins (ABPs) [4,5]
Cttn possesses an N-terminal acidic domain that interacts with the F-actin branching Arp2/3 complex, an actin-filament-binding region and a Src homology 3 (SH3) domain, which allows for interaction with other effectors of the actin cytoskeleton or scaffolding proteins [13]
Summary
Activity-dependent plasticity is associated with functional as well as structural changes at synapses and plays a vital role both during development and for cognitive functions as, for instance, processes of learning and memory formation [1,2,3]. Cttn possesses an N-terminal acidic domain that interacts with the F-actin branching Arp2/3 complex, an actin-filament-binding region and a Src homology 3 (SH3) domain, which allows for interaction with other effectors of the actin cytoskeleton or scaffolding proteins [13]. It is believed that Cttn contributes to both the activation and, in particular, the stabilization of Arp2/3 in branch junctions, yet the exact molecular mechanisms of its Arp2/3-dependent functions remain elusive. Arp2/3-dependent actin networks can form normally even in the absence of Cttn [19,20], suggesting that Cttn might serve a tuning function rather than being obligatory for Arp2/3 activation in vivo. Cttn might contribute to F-actin dynamics through Arp2/3-independent mechanisms as it has been shown to mediate GTPase activation through a yet unknown mechanism [19]
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