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Figure 1. Missense Mutations in Mouse Disc1
(A) Alignment of the predicted disrupted in schizophrenia 1 protein sequences of mouse Disc1 (ENSMUSP00000074147) and human DISC1 (ENSP00000295051) using the Clustal W 1.81 program. Residues identical between mouse and human have a gray background. The codon mutated in each Disc1 mutant mouse line is shown in red text and indicated by a red arrow. Nonsynonymous SNPs in human DISC1 associated with increased risk for major depression (Hashimoto et al., 2006 ), bipolar disorder (Maeda et al., 2006), schizophrenia (Callicott et al., 2005, Cannon et al., 2005), or schizoaffective disorder (Hodgkinson et al., 2004) are shown in green text and indicated by green arrows. The breakpoint of the translocation that segregates with psychiatric illness in a large Scottish family (Millar et al., 2000) is indicated by a vertical bar (|) labeled BP. Dashes indicate alignment gaps. Numbers to the right of the alignment show the amino acid position of the corresponding aligned sequence. Exons are indicated by alternating black and blue text.
(B) DNA sequence chromatograms showing point mutations in Disc1 Exon 2. Transversion 127A→T is predicted to convert residue 31 from CAG glutamine (Gln) to CTG leucine (Leu). Transition 334T→C is predicted to convert residue 100 from CTC leucine (Leu) to CCC proline (Pro).
Figure 2. Schizophrenic-like Behaviors in 31L and 100P Mutant Mice
(A) Prepulse inhibition of acoustic startle response. PPI assay using a combination of startle (120 dB) and three prepulse levels (69 dB, 73 dB, and 81 dB) in 31L/31L (n = 24), 31L/ (n = 24), 100P/100P (n = 21), 100P/ (n = 20), / (n = 21), and 31L/100P (n = 10) mice. PPI is expressed as the mean percent reduction (±SEM) in startle amplitude at all three prepulses. Higher y axis values represent greater percent PPI. There were significant effects of genotype (F(5,120) = 11.17, p = 0.0009), prepulse intensity (F(2,240) = 4.92, p = 0.008), and genotype-prepulse interaction (F(10,240) = 2.70, p = 0.004).  p < 0.05; p < 0.01; p < 0.001 versus / mice.
(B) Pharmacological responses in PPI assay. Mean effects of clozapine (3 mg/kg), haloperidol (0.4 mg/kg), bupropion (4 mg/kg), and rolipram (0.5 mg/kg) on PPI (±SEM) in 31L/31L (n = 10–16), 31L/ (n = 10–24), 100P/100P (n = 11–17), P/ (n = 10–22), and / (n = 11–16) mice. There were significant effects of genotype (F(4,290) = 23.40, p = 10
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