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Mol Psychiatry. 2019 Jan 4. doi: 10.1038/s41380-018-0338-4. [Epub ahead of print]

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B.

Author information

1
Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano, 390-8621, Japan.
2
Department of Zoology, Faculty of Science, Kafr Elsheikh University, Kafr Elsheihk, 33511, Egypt.
3
Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, 390-8621, Japan.
4
CREST, JST, Saitama, 332-0012, Japan.
5
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
6
Department of Molecular and Cellular Physiology, Institute of Medicine, Academic Assembly, Shinshu University, Nagano, 390-8621, Japan. ktabuchi@shinshu-u.ac.jp.
7
Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Nagano, 390-8621, Japan. ktabuchi@shinshu-u.ac.jp.
8
PRESTO, JST, Saitama, 332-0012, Japan. ktabuchi@shinshu-u.ac.jp.

Abstract

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-D-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the down-regulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons.

PMID:
30610199
DOI:
10.1038/s41380-018-0338-4

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