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

Mol Psychiatry. 2019 Jul;24(7):1079-1092. doi: 10.1038/s41380-018-0338-4. Epub 2019 Jan 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Calcium / metabolism
  • Calmodulin / metabolism
  • Female
  • Guanylate Kinases / deficiency*
  • Guanylate Kinases / metabolism
  • Guanylate Kinases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Protein Kinases / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / metabolism
  • Synaptic Transmission / physiology

Substances

  • Calmodulin
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Protein Kinases
  • CASK kinases
  • Guanylate Kinases
  • Calcium