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. 2019 Jan 4;24(7):1079–1092. doi: 10.1038/s41380-018-0338-4

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — The guanylate kinase domain of CASK is responsible for the disrupted E/I balance and NMDA receptor function in CASK-KD neurons. a–h Miniature postsynaptic currents of control and CASK-KD neurons co-transfected with or without various rescue constructs in layer 2/3 of the somatosensory cortex. Representative traces (a) and graphs of the frequency (b) and amplitude (c) of mEPSCs. Representative traces (d), summary graphs of the frequency (e), and amplitude (f) of mIPSCs. FL, full-length; ΔC, CAM domain deleted; ΔL, LIN domain deleted; ΔP, PDZ domain deleted; ΔS, SH3 domain deleted; ΔG and ΔGK, GK domain deleted; TA, T704A mutant of CASK. The CASK ΔG or TA constructs failed to rescue the increased frequency of mEPSCs (b) or the decreased frequency of mIPSCs (e) in CASK-KD neurons. Scale bars represent 10 pA (vertical axis) (a) and 20 pA (vertical axis) (d) and 1 s (horizontal axis) (a, d) (animal numbers; n = 3 in each condition). g Distribution of the frequency of mEPSCs versus mIPSCs for neurons of four genotypes. Each dot represents a single cell. h E/I balance index for neurons with each KD. i Representative traces of evoked AMPA (lower trace) and NMDA (upper trace) receptor-medicated synaptic currents in control and CASK-KD neurons. Scale bars represent 50 pA (vertical axis) and 0.2 s (horizontal axis). j Graph of the NMDA/AMPA ratio in control, CASK-KD, and CASK-KD + rescue vector-transfected neurons (animal numbers; n = 3 in each condition). k Normalized traces of NMDA receptor-mediated currents recorded from control and CASK-KD neurons were superimposed. Scale bar represents 0.2 s. l Weighted decay time constant (τ) of the NMDA receptor-mediated current in control, CASK-KD, and CASK-KD + rescue vector-transfected neurons. The decay time constant of the NMDA current was decreased in CASK-KD neurons, and was not rescued by CASKΔGK co-transfection. m The mRNA (left) and protein (middle) levels of GluN2A and GluN2B in control and CASK-KD neurons examined by qRT-PCR and immunoblot, respectively. Representative images (right) of immunoblot bands of β-actin, GluN2A, and GluN2B obtained from control and CASK-KD neurons (sample numbers; Cntl n = 3, shCASK n = 3 in mRNA; Cntl n = 5, shCASK n = 5 in protein). Statistical significance was determined by unpaired t test (m) or by ANOVA and Bonferroni’s post-hoc test (b, c, e, f, h, j, and l). *p < 0.05, **p < 0.01, and ***p < 0.001. Numbers on bars are the number of cells analyzed. N.S. not significant