Twelve studies to date report significant associations between certain haplotypes in the dysbindin gene and schizophrenia (SZ). Dysbindin was initially identified as a binding partner of the dystrobrevins, members of the dystrophin glycoprotein complex present in muscle and postsynaptic sites in the brain. Subsequent work has shown that dysbindin has additional binding partners, including several members of BLOC-1 (the biogenesis of lysosome-like organelles complex-1). We have found that dysbindin and several BLOC-1 proteins are frequently and significantly reduced in presynaptic fields of intrinsic glutamatergic projections of the hippocampal formation in SZ. The dysbindin reductions are inversely correlated with increased vesicular glutamate transporter-! (VGluT-1) immunoreactivity in the same projections. These alterations occur without apparent synaptic loss, alterations in (3-dystrobrevin, or evidence of neuroleptic effects on dysbindin or ? VGluT-1 We propose to investigate dysbindin in postmortem SZ brains and in the sandy (sdy) mouse, a mouse strain with a large deletion mutation in the dysbindin gene.
Our specific aims are designed to answer key questions about the generality, causes, and consequences of dysbindin reductions in SZ with a focus on its role in glutamate transmission.
In Aim 1, we map the regional distribution and isoform specificity of dysbindin reductions in SZ and correlate these with markers of several neurotransmitter systems.
In Aim 2, we investigate dysbindin gene expression as well as its relation to high risk haplotypes for SZ.
In Aim 3, we test the effects of reduced dysbindin on its BLOC-1 binding partners and hypothesized mechanisms by which reduced dysbindin alters glutamatergic synaptic machinery and glutamate release.
In Aim 4, we use high resolution imaging of voltage-sensitive dyes and whole cell patch and field recordings in the sdy mouse hippocampal formation to investigate the effects of the dysbindin negative mutation on neurotransmission, long term potentiation and long term depression in glutamatergic pathways. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH072880-02
Application #
7113694
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2005-08-18
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$418,061
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Glen Jr, W Bailey; Horowitz, Bryant; Carlson, Gregory C et al. (2014) Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning. Hippocampus 24:204-13
Larimore, Jennifer; Zlatic, Stephanie A; Gokhale, Avanti et al. (2014) Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes. J Biol Chem 289:14291-300
Balu, Darrick T; Carlson, Gregory C; Talbot, Konrad et al. (2012) Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. Hippocampus 22:230-40
Carlson, Gregory C; Talbot, Konrad; Halene, Tobias B et al. (2011) Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia. Proc Natl Acad Sci U S A 108:E962-70
Talbot, Konrad; Louneva, Natalia; Cohen, Julia W et al. (2011) Synaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location. PLoS One 6:e16886
Tang, Junxia; LeGros, Robert P; Louneva, Natalia et al. (2009) Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression. Hum Mol Genet 18:3851-63
Locke, Matthew; Tinsley, Caroline L; Benson, Matthew A et al. (2009) TRIM32 is an E3 ubiquitin ligase for dysbindin. Hum Mol Genet 18:2344-58
Talbot, Konrad (2009) The sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research. Prog Brain Res 179:87-94
Cox, M M; Tucker, A M; Tang, J et al. (2009) Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 8:390-7
Talbot, Konrad; Cho, Dan-Sung; Ong, Wei-Yi et al. (2006) Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum Mol Genet 15:3041-54