Figure 5. Profound Cortical Synaptic Defects Manifest in Mice Carrying the Schizophrenia-Associated R1117X Mutation.
(A–C) Typical AMPA receptor-mediated mEPSC recordings in the prefrontal cortex and statistical results for R1117X mice. n = 13 neurons for WT; n = 20 neurons for R1117X+/−; n = 18 neurons for R1117X+/+ from three pairs of mice. Note the highly significant reduction of mEPSC frequency in both heterozygous and homozygous mice and a modest reduction of amplitude in homozygotes.
(D–F) Typical AMPA receptor-mediated mEPSC recordings in the prefrontal cortex and statistical results for InsG3680 cohort. n = 18 neurons for WT; n = 16 neurons for InsG3680+/−; n = 17 neurons for InsG3680+/+ from three pairs of mice. Both heterozygous and homozygous mice display comparable miniature events to wild-type mice.
In (B), (C), (E), and (F), data are presented as mean ± SEM. *p < 0.05, **p < 0.01; one-way ANOVA with Bonferroni post hoc test.
(G and H) Representative confocal images of secondary dendrites of pyramidal neurons from frontal association area of mice with indicated genotypes (scale bar, 10 μm).
(I and J) Quantification of spine number from neurons with indicated genotypes from three littermate pairs indicates reduced spine numbers in R1117X+/−, R1117X+/+, and InsG3680+/+ mice.
(K and L) mRNAs of Shank3 homologs Shank1 and Shank2 are upregulated in cortical tissue from InsG3680+/+ compared to wild-type mice. Data are normalized to Gapdh mRNA and presented as mean ± SEM. WT mice (n = 5), R1117X+/+ mice (n = 5), and InsG3680+/+ mice (n = 5). In all the panels, data were collected from 2-month-old mice. In (I), (J), (K), and (L), *p < 0.05, **p < 0.01, **p < 0.001; one-way ANOVA with Bonferroni post hoc test.
(M) Representative blots for proteins detected by specific antibodies in the cortical SPM fraction from adult wild-type, R1117X+/+, and InsG3680+/+ mice.
(N) Adult InsG3680+/+ but not R1117X+/+ mice show increased Shank2 expression in cortical tissue. Quantification of relative levels of proteins as normalized to tubulin from cortical SPM. Data are presented as mean ± SEM *p < 0.05; one sample t test. (n = 8 samples per protein per genotype, each n being pooled tissue from two mice).