title: Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder.
abstract: BACKGROUND
  Synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) is an excitatory postsynaptic protein implicated in the pathogenesis of obsessive-compulsive behaviors. In mice, genetic deletion of Sapap3 causes obsessive-compulsive disorder (OCD)-like behaviors that are rescued by striatal expression of Sapap3, demonstrating the importance of striatal neurotransmission for the OCD-like behaviors. In the striatum, there are two main excitatory synaptic circuits, corticostriatal and thalamostriatal. Neurotransmission defects in either or both of these circuits could potentially contribute to the OCD-like behaviors of Sapap3 knockout (KO) mice. Previously, we reported that Sapap3 deletion reduces corticostriatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor-mediated synaptic transmission.
  
  
  METHODS
  Whole-cell electrophysiological recording techniques in acute brain slices were used to measure synaptic transmission in the corticostriatal and thalamostriatal circuits of Sapap3 KO mice and littermate control animals. Transgenic fluorescent reporters identified striatopallidal and striatonigral projection neurons. SAPAP isoforms at corticostriatal and thalamostriatal synapses were detected using immunostaining techniques.
  
  
  RESULTS
  In contrast to corticostriatal synapses, thalamostriatal synaptic activity is unaffected by Sapap3 deletion. At the molecular level, we find that another SAPAP family member, SAPAP4, is present at thalamostriatal, but not corticostriatal, synapses. This finding provides a molecular rationale for the functional divergence we observe between thalamic and cortical striatal circuits in Sapap3 KO mice.
  
  
  CONCLUSIONS
  These findings define the circuit-level neurotransmission defects in a genetic mouse model for OCD-related behaviors, focusing attention on the corticostriatal circuit for mediating the behavioral abnormalities. Our results also provide the first evidence that SAPAP isoforms may be localized to synapses according to circuit-selective principles.
authors: Department of Medicine, Division of Neurology, Durham, North Carolina.
authors: Yehong
authors: Y
authors: Wan
authors: Department of Medicine, Division of Neurology, Durham, North Carolina.
authors: Kristen K
authors: KK
authors: Ade
authors: Department of Medicine, Division of Neurology, Durham, North Carolina.
authors: Zachary
authors: Z
authors: Caffall
authors: Department of Cell Biology, Duke University, Durham, North Carolina.
authors: M
authors: M
authors: Ilcim Ozlu
authors: Department of Neurobiology, Durham, North Carolina; Department of Cell Biology, Duke University, Durham, North Carolina.
authors: Cagla
authors: C
authors: Eroglu
authors: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors: Guoping
authors: G
authors: Feng
authors: Department of Medicine, Division of Neurology, Durham, North Carolina; Department of Neurobiology, Durham, North Carolina. Electronic address: nicole.calakos@duke.edu.
authors: Nicole
authors: N
authors: Calakos
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D009771:Obsessive-Compulsive Disorder / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D013788:Thalamus / Q000503:physiopathology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C523020:Sapap3 protein, mouse; C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2
keywords: Corticostriatal; DLGAP3; GKAP; SAPAP3; obsessive-compulsive disorder; striatum; thalamostriatal