Human Molecular Genetics Advance Access originally published online on September 15, 2006
Human Molecular Genetics 2006 15(20):3041-3054; doi:10.1093/hmg/ddl246
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Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin
1 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA, 2 Department of Anatomy, National University of Singapore, 117597, Singapore and 3 Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
* To whom correspondence should be addressed at: Center for Neurobiology and Behavior, Translational Research Laboratories, Rm. 2213, 125 South 31st Street, Philadelphia, PA 19104-3403, USA. Tel: +1 215-573-2840; Fax: +1 215-573-2041; Email: sarnold{at}mail.med.upenn.edu.
Received June 27, 2006; Accepted September 5, 2006
Variations in the gene encoding the novel protein dysbindin-1 (DTNBP1) are among the most commonly reported genetic variations associated with schizophrenia. Recent studies show that those variations are also associated with cognitive functioning in carriers with and without psychiatric diagnoses, suggesting a general role for dysbindin-1 in cognition. Such a role could stem from the protein's known ability to affect neuronal glutamate release. How dysbindin-1 might affect glutamate release nevertheless remains unknown without the discovery of the protein's neuronal binding partners and its subcellular locus of action. We demonstrate here that snapin is a binding partner of dysbindin-1 in vitro and in the brain. Tissue fractionation of whole mouse brains and human hippocampal formations revealed that both dysbindin-1 and snapin are concentrated in tissue enriched in synaptic vesicle membranes and less commonly in postsynaptic densities. It is not detected in presynaptic tissue fractions lacking synaptic vesicles. Consistent with that finding, immunoelectron microscopy showed that dysbindin-1 is located in (i) synaptic vesicles of axospinous terminals in the dentate gyrus inner molecular layer and CA1 stratum radiatum and in (ii) postsynaptic densities and microtubules of dentate hilus neurons and CA1 pyramidal cells. The labeled synapses are often asymmetric with thick postsynaptic densities suggestive of glutamatergic synapses, which are likely to be derived from dentate mossy cells and CA3 pyramidal cells. The function of dysbindin-1 in presynaptic, postsynaptic and microtubule locations may all be related to known functions of snapin.
The authors wish it to be known that, in their opinion, the first 2 authors contributed equally to this work.
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