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. ? ? ?
