Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory

Samuel M. Cohen, Benjamin Suutari, Xingzhi He, Yang Wang, Sandrine Sanchez, Natasha N. Tirko, Nataniel J. Mandelberg, Caitlin Mullins, Guangjun Zhou, Shuqi Wang, Ilona Kats, Alejandro Salah, Richard W. Tsien () and Huan Ma ()
Additional contact information
Samuel M. Cohen: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Benjamin Suutari: NYU Langone Medical Center
Xingzhi He: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Yang Wang: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Sandrine Sanchez: NYU Langone Medical Center
Natasha N. Tirko: NYU Langone Medical Center
Nataniel J. Mandelberg: NYU Langone Medical Center
Caitlin Mullins: NYU Langone Medical Center
Guangjun Zhou: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Shuqi Wang: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine
Ilona Kats: NYU Langone Medical Center
Alejandro Salah: NYU Langone Medical Center
Richard W. Tsien: NYU Langone Medical Center
Huan Ma: and Department of Neurology of Second Affiliated Hospital, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04705-8

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