Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia

• Published in: Human molecular genetics Vol. 13; no. 21; pp. 2699 - 2708
• Main Authors: Numakawa, Tadahiro, Yagasaki, Yuki, Ishimoto, Tetsuya, Okada, Takeya, Suzuki, Tatsuyo, Iwata, Nakao, Ozaki, Norio, Taguchi, Takahisa, Tatsumi, Masahiko, Kamijima, Kunitoshi, Straub, Richard E., Weinberger, Daniel R., Kunugi, Hiroshi, Hashimoto, Ryota
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2004; Oxford Publishing Limited (England)
• Subjects: Adult; Alleles; Animals; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Cerebral Cortex - cytology; Chromones - pharmacology; Chromosomes, Human, Pair 6; Dysbindin; Dystrophin-Associated Proteins; Enzyme Inhibitors - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Glutamic Acid - secretion; Haplotypes; Humans; Linkage Disequilibrium; Male; Membrane Proteins - metabolism; Molecular and cellular biology; Morpholines - pharmacology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - physiology; Phosphatidylinositol 3-Kinases - drug effects; Phosphorylation; Polymorphism, Single Nucleotide; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred Strains; RNA, Small Interfering - metabolism; Schizophrenia - genetics; Synapsins - metabolism; Synaptosomal-Associated Protein 25; Japan; Psychosis; Schizophrenia; Genetics; Sensitivity; Neuron
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddh280

Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P=0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia.