Abstract
Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca2+/CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes (BDNF, c-Fos, Arc), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.
Highlights
Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist
To address questions surrounding the relevance of nuclear signaling for synaptic plasticity, gene expression and behavior, while avoiding ambiguous effects from the elimination or sequestration of multifunctional signaling molecules, we sought to manipulate the transport of the signaling protein while sparing the protein itself
We applied this strategy to the nuclear translocation of Ca2+/calmodulin (CaM)[18,19,24], which can switch on a nuclear-resident CaM kinase cascade, activating both cAMP response element binding protein (CREB) and CREB binding protein (CBP)
Summary
Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling This mutation is sufficient to disrupt gene expression and spatial learning in vivo. To address questions surrounding the relevance of nuclear signaling for synaptic plasticity, gene expression and behavior, while avoiding ambiguous effects from the elimination or sequestration of multifunctional signaling molecules, we sought to manipulate the transport of the signaling protein while sparing the protein itself We applied this strategy to the nuclear translocation of Ca2+/calmodulin (CaM)[18,19,24], which can switch on a nuclear-resident CaM kinase cascade, activating both CREB and CREB binding protein (CBP). Signaling to the nucleus by Ca2+/CaM translocation supports learning and memory and shows vulnerability in neuropsychiatric disease
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