[11C](R)-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live Disc1 locus-impaired mice

Maarten Ooms, Tetsuya Tsujikawa, Talakad G. Lohith, Sanché N. Mabins, Sami S. Zoghbi, Akiko Sumitomo, Hanna Jaaro-Peled, Yasuyuki Kimura, Sanjay Telu, Victor W. Pike, Toshifumi Tomoda, Robert B. Innis, Akira Sawa, Masahiro Fujita

Research output: Contribution to journalArticle

Abstract

Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C](R)-Rolipram binding was measured by PET in LI (n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [11C](R)-Rolipram total distribution volumes (VT) were calculated and corrected for plasma-free fraction (fP) measured in a separate group of LI (n = 6) and WT (n = 7) mice. PDE4 enzyme activity was measured using in vitro samples of cerebral cortices from groups of LI (n = 4), heterozygote (n = 4), and WT (n = 4) mice. Disc1 LI mice showed a 41% increase in VT (18 ± 6 vs. 13±4 mL/cm3, P = 0.04) compared to WT mice. VT/fP showed a 73% significant increase (90 ± 31 vs. 52 ± 15 mL/cm3, P = 0.004) in Disc1 LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences (p < 0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [11C](R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4–DISC1 interaction.

LanguageEnglish (US)
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Type 4 Cyclic Nucleotide Phosphodiesterase
Rolipram
Positron-Emission Tomography
Schizophrenia
Proteins
Phosphodiesterase 4 Inhibitors
Enzyme Assays
Heterozygote
Inhibition (Psychology)
Cerebral Cortex
Protein Isoforms
Enzymes

Keywords

  • disrupted in schizophrenia
  • locus impairment mouse model
  • phosphodiesterase 4
  • Positron emission tomography
  • [C](R)-Rolipram

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

[11C](R)-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live Disc1 locus-impaired mice. / Ooms, Maarten; Tsujikawa, Tetsuya; Lohith, Talakad G.; Mabins, Sanché N.; Zoghbi, Sami S.; Sumitomo, Akiko; Jaaro-Peled, Hanna; Kimura, Yasuyuki; Telu, Sanjay; Pike, Victor W.; Tomoda, Toshifumi; Innis, Robert B.; Sawa, Akira; Fujita, Masahiro.

In: Journal of Cerebral Blood Flow and Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Ooms, Maarten ; Tsujikawa, Tetsuya ; Lohith, Talakad G. ; Mabins, Sanché N. ; Zoghbi, Sami S. ; Sumitomo, Akiko ; Jaaro-Peled, Hanna ; Kimura, Yasuyuki ; Telu, Sanjay ; Pike, Victor W. ; Tomoda, Toshifumi ; Innis, Robert B. ; Sawa, Akira ; Fujita, Masahiro. / [11C](R)-Rolipram positron emission tomography detects DISC1 inhibition of phosphodiesterase type 4 in live Disc1 locus-impaired mice. In: Journal of Cerebral Blood Flow and Metabolism. 2018.
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AU - Ooms, Maarten

AU - Tsujikawa, Tetsuya

AU - Lohith, Talakad G.

AU - Mabins, Sanché N.

AU - Zoghbi, Sami S.

AU - Sumitomo, Akiko

AU - Jaaro-Peled, Hanna

AU - Kimura, Yasuyuki

AU - Telu, Sanjay

AU - Pike, Victor W.

AU - Tomoda, Toshifumi

AU - Innis, Robert B.

AU - Sawa, Akira

AU - Fujita, Masahiro

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AB - Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C](R)-Rolipram binding was measured by PET in LI (n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [11C](R)-Rolipram total distribution volumes (VT) were calculated and corrected for plasma-free fraction (fP) measured in a separate group of LI (n = 6) and WT (n = 7) mice. PDE4 enzyme activity was measured using in vitro samples of cerebral cortices from groups of LI (n = 4), heterozygote (n = 4), and WT (n = 4) mice. Disc1 LI mice showed a 41% increase in VT (18 ± 6 vs. 13±4 mL/cm3, P = 0.04) compared to WT mice. VT/fP showed a 73% significant increase (90 ± 31 vs. 52 ± 15 mL/cm3, P = 0.004) in Disc1 LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences (p < 0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [11C](R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4–DISC1 interaction.

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