Association of the Ser⁷⁰⁴Cys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding

Abstract

A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser 704 Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser 704 Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser ⁄ Ser subjects exhibited greater engagement of the HF together with greater HF-dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser 704 Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.

DISC1 gene and affective psychopathology: A combined structural and functional MRI study

“…In agreement with a previous report (Di Giorgio et al, 2008), we demonstrated that healthy Cys-carriers had smaller parahippocampal gyrus (PHG) and hippocampal volume than healthy Ser-homozygotes. The PHG has an important role in episodic memory (de Curtis and Pare.…”

“…Groups did not differ in genotype distribution (c 2 (6) ¼ 3.36, p ¼ 0.76). We compared Cys-carriers (Cys/Cys-and Cys/Ser-genotypes) with Ser-homozygotes, based on the small amount of Cys-homozygotes and in agreement with the literature (Hashimoto et al, 2006;Callicott et al, 2005;Di Giorgio et al, 2008;Prata et al, 2008;Brauns et al, 2011;Takahashi et al, 2009). …”

“…Therefore, altered hippocampal and PFC function during these processes could serve as promising endophenotypes in studying the association between DISC1-genotype and affective disorders. Supportive of this suggestion, in healthy people, the Cys-allele of the Ser704Cys SNP has been associated with less hippocampal activation during working memory (WM) and more hippocampal activation during episodic memory (Callicott et al, 2005), and with less activation of the dorsolateral prefrontal cortex (DLPFC) during both memory (Di Giorgio et al, 2008) and executive functioning . Moreover, smaller hippocampus (Di Giorgio et al, 2008) and anterior cingulate cortex (ACC) volume (Hashimoto et al, 2006) have been demonstrated in Cys-carriers, whereas larger DLPFC volume has been observed (Brauns et al, 2011;Takahashi et al, 2009).…”

Episodic Memory in Schizophrenia

“…Another group investigated the same SNP, but their findings were not convergent with those of the Callicott group (Di Giorgio et al 2008). Eighty healthy controls were scanned during encoding and retrieval of novel, complex scenes of neutral emotional valence.…”

Molecular Characterization of Disrupted in Schizophrenia-1 Risk Variant S704C Reveals the Formation of Altered Oligomeric Assembly

“…One of the natural schizophrenia risk DISC1 polymorphisms, S704C (10,11), shown to affect the function of prefrontal cortex, is also localized in its C-terminal domain (12,13). This SNP has been observed to function at the molecular level, as DISC1-S704C affects the localization of key PCM1 (pericentriolar material protein-1) to the centrosome (14).…”