title: Potential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice.
abstract: Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein encoded by DTNBP1, dysbindin-1, is expressed in forebrain neurons where it interacts with proteins mediating vesicular trafficking and exocytosis. It has been shown that loss of dysbindin-1 results in a decrease in glutamate release in the prefrontal cortex; however the mechanisms underlying this decrease are not fully understood. In order to investigate this question, we evaluated dysbindin-1 null mutant mice, using electrophysiological recordings of prefrontal cortical neurons, imaging studies of vesicles, calcium dynamics and Western blot measures of synaptic proteins and Ca(2+) channels. Dysbindin-1 null mice showed a decrease in the ready releasable pool of synaptic vesicles, decreases in quantal size, decreases in the probability of release and deficits in the rate of endo- and exocytosis compared with wild-type controls. Moreover, the dysbindin-1 null mice show decreases in the [Ca(2+)]i,expression of L- and N-type Ca(2+)channels and several proteins involved in synaptic vesicle trafficking and priming. Our results provide new insights into the mechanisms of action of dysbindin-1.
authors.affiliation: Dept of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saggu
authors.forename: Tyrone D
authors.initials: TD
authors.lastname: Cannon
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
authors.forename: Antonieta
authors.initials: A
authors.lastname: Lavin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology; D011336:Probability; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C073804:FM1 43; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D018698:Glutamic Acid; D011189:Potassium Chloride; D002118:Calcium