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.
Highlights
These authors contributed : Takuma Mori, Enas A
To examine the physiological role of calmodulin-dependent serine protein kinase (CASK), we studied the effect of CASK-KO in adult mouse brain
We found that approximately half (46.6 %) of these neurons expressed CASK messenger RNA while half did not (Fig. 1g), suggesting that CASK was subjected to X-chromosome inactivation (XCI)
Summary
CASK interacts with other synaptic proteins involved in cell adhesion, cytoskeletal organization, signal transduction, and/or gene transcription [4,5,6,7,8,9,10,11,12], and is thought to have both pre- and postsynaptic functions. The inactivated and activated pair of X-chromosomes is transmitted to daughter cells after every cell division, resulting in a random mixture of cells with two different X genotypes throughout the body Both CASK-intact and CASK-deficient cells are likely to be distributed in a mosaic pattern in the brain of affected females. Rescue experiments in CASK-KD neurons showed that this disrupted E/I balance was due to the down-regulation of GluN2B transcription, which is normally promoted by the cooperation of TBR1 and CASK
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