Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy - PubMed (original) (raw)

Comparative Study

. 2012 Jul 24;109(30):12165-70.

doi: 10.1073/pnas.1206118109. Epub 2012 Jun 11.

Yanhong Wang, Yoshitatsu Sei, Patricio O'Donnell, Patrick Piantadosi, Francesco Papaleo, Richard E Straub, Wenwei Huang, Craig J Thomas, Radhakrishna Vakkalanka, Aaron D Besterman, Barbara K Lipska, Thomas M Hyde, Paul J Harrison, Joel E Kleinman, Daniel R Weinberger

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Comparative Study

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

Amanda J Law et al. Proc Natl Acad Sci U S A. 2012.

Abstract

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

(A) Increased expression of ErbB4 CYT-1 mRNA [*F(5, 50) = 3.81; P = 0.04] and decreased ErbB3 in patients with schizophrenia (n = 23) compared with normal control subjects (n = 32) [*F(1, 55) = 3.80; P = 0.045]. (B) Association between ErbB4 risk haplotype (AGG; rs7598440; rs839523; rs707284) and ErbB4 CYT-1 levels in the whole cohort [F(5, 50) = 4.00; P = 0.012] (AGG/AGG, n = 13; AGG/nonrisk, n = 28; nonrisk/nonrisk, n = 14). (C) Increased expression of PIK3CD (**β = 0.41; t = 3.20, P ≤ 0.002) and PIK3R3 (*β = 0.26; t = 1.97, P ≤ 0.025) in patients with schizophrenia (n = 23) compared with normal control subjects (n = 32). (D) PIK3CD expression in normal and patient-derived LCLs is associated with an ErbB4 risk haplotype (**β = −0.32; t = −2.57, P ≤ 0.01). (E and F) NRG1-stimulated intracellular [PI(3,4,5)P3] production is (E) reduced in schizophrenia (*β = −0.27; t = −1.89, P ≤ 0.032; n = 29 vs.19) and (F) associated with ErbB4 risk haplotype [*β = −0.41; t = −3.01, P ≤ 0.004; whole sample (AGG/AGG, n = 11; AGG/nonrisk, n = 23; nonrisk/nonrisk, n = 13)]. Values are mean ± SEM.

Fig. 2.

Fig. 2.

(A) The effect of i.p. injection of the p110δ inhibitor [IC87114] (0.1 mg/kg) 30 min before amphetamine injection (0.75 mg/kg or 1.5 mg/kg) on locomotion in the mouse showed a significant interaction with amphetamine dose and time [treatment × dose × time (F(14, 308) = 3.04; P = 0.0002): solid circle, IC87114 pretreatment, 1.5 mg/kg amphetamine, n = 7; solid triangle, vehicle pretreatment, 1.5 mg/kg amphetamine, n = 7; open triangle, vehicle pretreatment, 0.75 mg/kg amphetamine, n = 7; open circle, IC87114 pretreatment, 0.75 mg/kg amphetamine, n = 7]. Posthoc tests revealed that pretreatment with IC87114 abolished the hyperlocomotor effects of 1.5 mg/kg amphetamine (*P < 0.05 vs. IC87114 pretreatment; #P < 0.05, 1.5 mg/kg amphetamine vs. 0.75 mg/kg amphetamine). No effects of IC87114 were observed on normal baseline locomotor activity (Inset: solid triangle, IC87114, n = 19; open circle, vehicle, n = 18). (B) Acute IC87114 treatment in mouse (0.1 mg/kg) increases phosphorylation of AKT at Thr308 (*P ≤ 0.05). Striatum, n = 4 per group. (C) Effect of pretreatment with IC87114 (0.1 mg/kg) 30 min before apomorphine injection on PPI in the NVHL rat model showed a highly significant interaction with lesion status [Treatment × lesion: F(1, 112) = 13.81, P < 0.00001]. Posthoc tests revealed significant improvement of PPI in NVHL rats treated with IC87114 compared with vehicle [F(1, 56) = 7.3, P < 0.009] and no significant effect of IC87114 on sham-operated rats [F(1, 55) = 7.3, P = 0.085]. Main effects of lesion status (F = 9.33; P = 0.003) and prepulse intensity (F = 20.78; P < 0.00001) were also observed on PPI, whereby PPI progressively increased with higher prepulse intensities and NVHL rats had reduced PPI compared with controls. n = 9–11 rats per group. Mean ± SEM.

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