Science Topics – 122

De novo CaMKIIα/β mutants causing neurodevelopmental disorders upregulate A-type voltage-dependent K + currents in hippocampal neurons.
1Tenpei Akita, 2Kazushi Aoto, 3Mitsuhiro Kato (4Naomichi Matsumoto, 2Hirotomo Saitsu)

α and β isoforms of calcium/calmodulin-dependent protein kinase II (CaMKII) play a key role in neuronal plasticity in the postnatal brain. By whole exome sequencing of 976 patients with neurodevelopmental disorders, we identified de novo mutations in the genes encoding CaMKIIα/β in five patients. All the patients exhibit delayed motor development and intellectual disability, and four of them also suffer from epileptic seizures. Mapping the mutation sites on crystal structures of human CaMKIIα proteins predicted that all the mutations would impair the binding of the regulatory segment of CaMKII to its kinase domain, thereby inhibiting autoinhibition of the kinase activity under resting conditions. Indeed, the basal kinase activity was increased in three mutants, because of release from autoinhibition. Transfection of primary hippocampal neurons with a CaMKIIα mutant (p.Pro212Gln) caused accelerated repolarization of single action potential spikes in transfected neurons, and this was due to the enhanced A-type voltage-dependent K + current mediated by Kv4 channels. The basal amplitude of miniature excitatory post-synaptic currents was, however, unchanged in the transfected neurons. The increased A current would suppress post-synaptic depolarization, especially caused by back-propagating action potentials, in pyramidal neurons. This would limit plastic changes of synaptic functions, and this might lead to neurodevelopmental disorders in the patients.

Akita T*, Aoto K*, Kato M* (*equal contribution), Shiina M, Mutoh H, Nakashima M, Kuki I, Okazaki S, Magara S, Shiihara T, Yokochi K, Aiba K, Tohyama J, Ohba C, Miyatake S, Miyake N, Ogata K, Fukuda A, Matsumoto N, Saitsu H (corresponding authors).
De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders. Annals of Clinical and Translational Neurology 5(3):280–296, 2018.

<Figure Legends>
Left) Comparison of A-type K+ currents in primary hippocampal neurons expressing wild-type and mutant CaMKIIα (the proline at 212 was replaced with glutamine). Two different protocols of voltage steps (uppermost) were applied to the same neurons, and A currents were derived by subtracting the current response II from the response I. Right) A possible effect of increased Kv4-mediated A currents in mutant-expressing neurons. In hippocampal pyramidal neurons, Kv4 channels are concentrated in dendritic arbors, and play a role in regulating post-synaptic depolarization, especially caused by back-propagating action potentials, which is necessary for synaptic plasticity. The increased A currents would suppress the post-synaptic depolarization much stronger than normal, thereby reducing Ca2+ entry via NMDA receptors and/or voltage-gated Ca2+ channels and limiting synaptic plasticity.

1 Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
2 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
3 Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan
4 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan