Year-end Sale % OFF 
Abstract
The roles of calcium-calmodulin-dependent protein kinase II-alpha (CaMKIIα) in the expression of long-term synaptic plasticity in the adult brain have been extensively studied. However, how increased CaMKIIα activity controls the maturation of neuronal circuits remains incompletely understood. Herein, we show that pyramidal neurons without CaMKIIα activity upregulate the rate of spine addition, resulting in elevated spine density. Genetic elimination of CaMKIIα activity specifically eliminated the observed maturation-dependent suppression of spine formation. Enhanced spine formation was associated with the stabilization of actin in the spine and could be reversed by increasing the activity of the small GTPase Rap1. CaMKIIα activity was critical in the phosphorylation of synaptic Ras GTPase-activating protein (synGAP), the dispersion of synGAP from postsynaptic sites, and the activation of postsynaptic Rap1. CaMKIIα is already known to be essential in learning and memory, but our findings suggest that CaMKIIα plays an important activity-dependent role in restricting spine density during postnatal development.
Highlights
Calcium-calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase that is highly expressed in the brain[1]
We have provided evidence showing that CaMKIIα activity plays an indispensable role in restricting the density of spines on hippocampal pyramidal neurons during postnatal development
This CaMKIIα-dependent regulation is based on activity-driven suppression of increased spine development and is mediated by actin destabilization through the small GTPase Rap[1], which may be functionally regulated by synaptic Ras GTPase-activating protein (synGAP) molecules
Summary
Calcium-calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase that is highly expressed in the brain[1]. Previous studies produced evidential support for the roles of plasticity-associated molecules in spine remodelling in the developing cortex[9] Of these plasticity-related signalling mechanisms, NMDA receptor-dependent signalling has been shown to be essential in long-term changes in synaptic functions and structures[10]. We previously generated knock-in mice lacking kinase activity but with physiological expression of a mutated CaMKIIα protein (K42R)[19] This mouse model should be useful in detecting the regulatory functions of CaMKIIα-dependent signalling pathways in the development and maturation of synaptic connectivity in the mouse forebrain. The combination of the late onset of CaMKIIα accumulation, the important role of CaMKIIα in synaptic plasticity, and the involvement of NMDA receptor-dependent signalling in proper cortical neuron wiring led us to perform detailed structural analyses of dendritic spine development in hippocampal slice cultures from CaMKIIα (K42R) knock-in mice (CaMKIIα KI mice). Our findings suggest that gradual increases in CaMKIIα activity in the postnatal forebrain may be effective in suppressing the rapid increase in spine synapse density via the activation of Rap[1] signalling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
