Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin.
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.
Talbot
Konrad
K
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cho
Dan-Sung
DS
Ong
Wei-Yi
WY
Benson
Matthew A
MA
Han
Li-Ying
LY
Kazi
Hala A
HA
Kamins
Joshua
J
Hahn
Chang-Gyu
CG
Blake
Derek J
DJ
Arnold
Steven E
SE
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D001923:Brain Chemistry; D019556:COS Cells; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002522:Chlorocebus aethiops; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005260:Female; D006624:Hippocampus / Q000737:chemistry; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D012559:Schizophrenia / Q000378:metabolism; D013572:Synaptic Vesicles / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000378:metabolism*
D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C118519:SNAPIN protein, human; D033921:Vesicular Transport Proteins