Analysis of strain-dependent prepulse inhibition points to a role for Shmt1 (SHMT1) in mice and in schizophrenia

Motoko Maekawa, Tetsuo Ohnishi, Kenji Hashimoto, Akiko Watanabe, Yoshimi Iwayama, Hisako Ohba, Eiji Hattori, Kazuo Yamada, Takeo Yoshikawa

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Deficits in prepulse inhibition (PPI) are known in mental illnesses, including schizophrenia. NMDA receptor function affects PPI integrity and d-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both d-serine synthesizing enzyme and enzyme for reversible conversion between glycine and l-serine (Srr and Shmt1, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to schizophrenia. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of d-serine and glycine from the dialysate was higher in B6, compared to C3. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to C3 conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of schizophrenia and genetic associations with the disease. The SHMT1 levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to schizophrenia.

Original languageEnglish
Pages (from-to)1374-1385
Number of pages12
JournalJournal of Neurochemistry
Issue number6
Publication statusPublished - 2010 Dec
Externally publishedYes


  • NMDA receptor
  • d-serine
  • endophenotype
  • glycine
  • serine hydroxymethyltransferase 1
  • serine racemase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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