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CELLULAR TRAFFICKING IN SCHIZOPHRENIA: IS IT IMPORTANT?
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
were rated as having good functional outcome. In the CHR sample for the non-converters 70% had good role and 71% good social functioning and for the converters at their final assessments 21% had good social functioning and 33% good role functioning. For FEP predictors of good functioning were significantly lower levels of positive and negative symptoms at all times, less depression overall, more improvement over the course of their treatment, shorter DUP and higher levels of premorbid and baseline social and role functioning. For the non-converting CHR participants the predictors of later good functioning were low levels of negative symptoms at all assessments, and good premorbid functioning. Although the level of attenuated positive symptoms did not differ between the two CHR groups those in the good functioning group had less disorganized communication. Similar to the non-converters, converters with good functioning had less negative symptoms and better premorbid functioning. For those at the FEP DUP, previous level of functioning and clinical symptoms were the variables that were related to good functional outcome. CHR individuals typically present with poor social functioning relative to normal controls, even when they do not go on to develop a psychotic illness within 1-2 years. A proportion do however have good functioning and predictors of good functioning at the period of risk were similar to the FEP, namely premorbid functioning and lack of negative symptoms. These data suggest that the course of functional outcome may be already set prior to even the onset of early subthreshold symptoms.
Symposium CELLULAR TRAFFICKING IN SCHIZOPHRENIA: IS IT IMPORTANT? Chairpersons: David R. Cotter and James Meador-Woodruff Discussant: William G. Honer Sunday, 15 April 2012 4:15 pm – 6:15 pm Overall Abstract: A wealth of data is converging to indicate that cellular trafficking is abnormal in schizophrenia. As cellular trafficking may be amenable to pharmacological intervention the characterization of deficits in the process has potential downstream implications to therapy. This symposium brings together 4 speakers who approach the issue of trafficking in schizophrenia from 4 different angles. Intriguingly, three different mechanisms which may underlie diminished NMDA receptor function in schizophrenia through altered trafficking are discussed. Volker Hauke begins the symposium by outlining the basic biology of clathrin mediated endocytosis (CME) and how synaptic plasticity is regulated by endocytic proteins and how this is relevant to neuropsychiatric disorders. Professor Hauke’s data shows that the endocytic protein stonin 2 has a core role in presynaptic plasticity, and how the behaviour of stonin 2 mutants models features of schizophrenia. David Cotter will report on his proteomic studies which have implicated CME in schizophrenia. He will discuss how dysregulation of CME may influence NMDA receptor (NR) recycling and NR hypofunction in schizophrenia. He will then give an overview of the evidence implicating the clathrin interactome more generally in psychosis, including the evidence of genetic studies and studies showing that antipsychotic agents modulate CME. Chang-Gyu Hahn also focuses on the molecular underpinnings for attenuated NR function in schizophrenia. As synaptic NR complexes reside in the postsynaptic density (PSD) Dr Hahn evaluated NR complexes in the postmortem prefrontal cortex of schizophrenia which was enriched for the PSD. He found that the NR1 subunit was significantly enhanced in the schizophrenia group and that the C2’ isoform of the NR1, which binds PSD-95 with higher affinity than the other NR1 isoforms was specifically upregulated. These findings suggest an alternative mechanism for altered trafficking of NR1, namely, one mediated by over-representation of the C2’ isoform. Jim Meador-Woodruff extends the theme further by exploring an alternative potential basis for abnormalities of intracellular trafficking of glutamate receptors in schizophrenia. He describes that recent studies show that palmitoylation of synaptic proteins regulates protein trafficking and he provides evidence that there is a profound diminution in extent of palmitoylation of many proteins in schizophrenia. He suggests that altered palmitoylation of NR may represent a basis for abnormal NR trafficking in schizophrenia. Paul Harrison will lead the discussion by integrating the discussions drawing on his expertise in the fields of schizophrenia neuropathology, neuroscience and, specifically, of NR function. A focus of the discussion, clearly led by the findings presented, will lie
S15
in the consideration that altered trafficking in schizophrenia may represent a common functional endpoint of many different molecular abnormalities. We will end with a discussion of future direction for research which will include the potential to develop new treatments based on the modulation of cellular trafficking.
PLASTIC MODULATION OF NEUROTRANSMISSION BY ENDOCYTIC SORTING OF SYNAPTIC VESICLE PROTEINS Volker Haucke 1,2 , Natalia Kononenko 1,2 , Takeshi Sakaba 4 , M. Kasim Diril 1 , Michael Kintscher 2 , Jan Schmoranzer 1 , Seong Joo Koo 1 , Gerit Pfuhl 3 , York Winter 3 , Dietmar Schmitz 2 , Tanja Maritzen 1 1 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; 2 NeuroCure Cluster of Excellence, Charité Berlin, Charitéplatz, Berlin, Germany; 3 Humboldt Universität zu Berlin, Cognitive Neurobiology, Berlin, Germany; 4 Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany Synaptic transmission involves the calcium-regulated fusion of synaptic vesicles (SVs), a process that depends on the SV calcium sensor synaptotagmin (Syt) [1,2] and is plastically modulated by components of the active zone (AZ) that define sites of neurotransmitter release [3]. Genetic data link defects in short-term plasticity to neuropsychiatric disorders such as autism, epilepsy, and schizophrenia [4]. Following exocytosis surface-stranded SV proteins need to be gathered by endocytic adaptors to re-assemble SVs of the correct size and composition [5]. The precise mechanism by which SVs are reformed is unknown and may involve retrieval of SV protein clusters [6] and/or cargo-specific recognition of select SV proteins by endocytic adaptors [7] such as AP2, AP180, stonin 2 (Stn2) [8], or endophilin [9]. We show that endocytic sorting of the synaptic vesicle calcium sensor synaptotagmin 1 by stonin 2 alters short-term plasticity. Stonin 2 knockout mice display increases in synaptic vesicle pool size and short-term facilitation at mossy fibers. Furthermore, Stn2 KO mice displayed increased explorative activity, were more active in the y-maze, and showed increased vertical locomotion. Moreover, when exploring an open field arena, Stn2 mice had a shorter latency towards the placed object. Thus, loss of Stn2 causes increased locomotion- and exploration-related behaviors in mice. This phenotype resembles arousal seeking and impulsivity observed in patients suffering from Tourette syndrome or schizophrenia, neuropsychiatric disorders linked to mutations in Stn2 in humans [10]. These alterations are paired with a partial redistribution of synaptotagmin 1 to the neuronal surface and to active zones while synaptic vesicle endocytosis remains unaffected. A similar coupling between exocytosis and endocytic membrane retrieval is required for the rapid replenishment of release-ready vesicles at active zones at the calyx of Held, a process that depends on the Stn2-associated endocytic scaffold intersectin. Collectively, our data reveal a novel role for endocytic proteins in the modulation of presynaptic plasticity and suggest potential mechanisms by which defective endocytic sorting of SV proteins might cause neurological disorders. References: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Chapman ER, Annu Rev Biochem 77, 615 (2008). Jahn R, Nat Rev Mol Cell Biol 7, 631 (Sep, 2006). Sudhof TC, Science 323, 474 (Jan 23, 2009). Powell CM, Neurobiol Learn Mem 85, 2 (Jan, 2006). Hauck V, Nat Rev Neurosci 12, 127 (Mar, 2011). Opazo F, et al., Traffic 11, 800 (Jun, 2010). Fernandez-Alfonso T, Neuron 51, 179 (Jul 20, 2006). Diril MK, Haucke V, Dev Cell 10, 233 (Feb, 2006). Voglmaier SM, et al., Neuron 51, 71 (Jul 6, 2006). Breedveld GJ, Neurogenetics 11, 417 (Oct, 2010).
CLATHRIN-MEDIATED-ENDOCYTOSIS AND CLATHRIN-DEPENDENT MEMBRANE AND PROTEIN TRAFFICKING; CORE PATHOPHYSIOLOGICAL PROCESSES IN SCHIZOPHRENIA AND BIPOLAR DISORDER? David R. Cotter, Klaus Oliver Schubert, Melanie Föcking Department of Psychiatry, Royal College of Surgeons in Ireland, Smurfit Building, Beaumont Hospital, Dublin, Ireland Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane- and protein trafficking. It is critical
were rated as having good functional outcome. In the CHR sample for the non-converters 70% had good role and 71% good social functioning and for the converters at their final assessments 21% had good social functioning and 33% good role functioning. For FEP predictors of good functioning were significantly lower levels of positive and negative symptoms at all times, less depression overall, more improvement over the course of their treatment, shorter DUP and higher levels of premorbid and baseline social and role functioning. For the non-converting CHR participants the predictors of later good functioning were low levels of negative symptoms at all assessments, and good premorbid functioning. Although the level of attenuated positive symptoms did not differ between the two CHR groups those in the good functioning group had less disorganized communication. Similar to the non-converters, converters with good functioning had less negative symptoms and better premorbid functioning. For those at the FEP DUP, previous level of functioning and clinical symptoms were the variables that were related to good functional outcome. CHR individuals typically present with poor social functioning relative to normal controls, even when they do not go on to develop a psychotic illness within 1-2 years. A proportion do however have good functioning and predictors of good functioning at the period of risk were similar to the FEP, namely premorbid functioning and lack of negative symptoms. These data suggest that the course of functional outcome may be already set prior to even the onset of early subthreshold symptoms.
Symposium CELLULAR TRAFFICKING IN SCHIZOPHRENIA: IS IT IMPORTANT? Chairpersons: David R. Cotter and James Meador-Woodruff Discussant: William G. Honer Sunday, 15 April 2012 4:15 pm – 6:15 pm Overall Abstract: A wealth of data is converging to indicate that cellular trafficking is abnormal in schizophrenia. As cellular trafficking may be amenable to pharmacological intervention the characterization of deficits in the process has potential downstream implications to therapy. This symposium brings together 4 speakers who approach the issue of trafficking in schizophrenia from 4 different angles. Intriguingly, three different mechanisms which may underlie diminished NMDA receptor function in schizophrenia through altered trafficking are discussed. Volker Hauke begins the symposium by outlining the basic biology of clathrin mediated endocytosis (CME) and how synaptic plasticity is regulated by endocytic proteins and how this is relevant to neuropsychiatric disorders. Professor Hauke’s data shows that the endocytic protein stonin 2 has a core role in presynaptic plasticity, and how the behaviour of stonin 2 mutants models features of schizophrenia. David Cotter will report on his proteomic studies which have implicated CME in schizophrenia. He will discuss how dysregulation of CME may influence NMDA receptor (NR) recycling and NR hypofunction in schizophrenia. He will then give an overview of the evidence implicating the clathrin interactome more generally in psychosis, including the evidence of genetic studies and studies showing that antipsychotic agents modulate CME. Chang-Gyu Hahn also focuses on the molecular underpinnings for attenuated NR function in schizophrenia. As synaptic NR complexes reside in the postsynaptic density (PSD) Dr Hahn evaluated NR complexes in the postmortem prefrontal cortex of schizophrenia which was enriched for the PSD. He found that the NR1 subunit was significantly enhanced in the schizophrenia group and that the C2’ isoform of the NR1, which binds PSD-95 with higher affinity than the other NR1 isoforms was specifically upregulated. These findings suggest an alternative mechanism for altered trafficking of NR1, namely, one mediated by over-representation of the C2’ isoform. Jim Meador-Woodruff extends the theme further by exploring an alternative potential basis for abnormalities of intracellular trafficking of glutamate receptors in schizophrenia. He describes that recent studies show that palmitoylation of synaptic proteins regulates protein trafficking and he provides evidence that there is a profound diminution in extent of palmitoylation of many proteins in schizophrenia. He suggests that altered palmitoylation of NR may represent a basis for abnormal NR trafficking in schizophrenia. Paul Harrison will lead the discussion by integrating the discussions drawing on his expertise in the fields of schizophrenia neuropathology, neuroscience and, specifically, of NR function. A focus of the discussion, clearly led by the findings presented, will lie
S15
in the consideration that altered trafficking in schizophrenia may represent a common functional endpoint of many different molecular abnormalities. We will end with a discussion of future direction for research which will include the potential to develop new treatments based on the modulation of cellular trafficking.
PLASTIC MODULATION OF NEUROTRANSMISSION BY ENDOCYTIC SORTING OF SYNAPTIC VESICLE PROTEINS Volker Haucke 1,2 , Natalia Kononenko 1,2 , Takeshi Sakaba 4 , M. Kasim Diril 1 , Michael Kintscher 2 , Jan Schmoranzer 1 , Seong Joo Koo 1 , Gerit Pfuhl 3 , York Winter 3 , Dietmar Schmitz 2 , Tanja Maritzen 1 1 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany; 2 NeuroCure Cluster of Excellence, Charité Berlin, Charitéplatz, Berlin, Germany; 3 Humboldt Universität zu Berlin, Cognitive Neurobiology, Berlin, Germany; 4 Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany Synaptic transmission involves the calcium-regulated fusion of synaptic vesicles (SVs), a process that depends on the SV calcium sensor synaptotagmin (Syt) [1,2] and is plastically modulated by components of the active zone (AZ) that define sites of neurotransmitter release [3]. Genetic data link defects in short-term plasticity to neuropsychiatric disorders such as autism, epilepsy, and schizophrenia [4]. Following exocytosis surface-stranded SV proteins need to be gathered by endocytic adaptors to re-assemble SVs of the correct size and composition [5]. The precise mechanism by which SVs are reformed is unknown and may involve retrieval of SV protein clusters [6] and/or cargo-specific recognition of select SV proteins by endocytic adaptors [7] such as AP2, AP180, stonin 2 (Stn2) [8], or endophilin [9]. We show that endocytic sorting of the synaptic vesicle calcium sensor synaptotagmin 1 by stonin 2 alters short-term plasticity. Stonin 2 knockout mice display increases in synaptic vesicle pool size and short-term facilitation at mossy fibers. Furthermore, Stn2 KO mice displayed increased explorative activity, were more active in the y-maze, and showed increased vertical locomotion. Moreover, when exploring an open field arena, Stn2 mice had a shorter latency towards the placed object. Thus, loss of Stn2 causes increased locomotion- and exploration-related behaviors in mice. This phenotype resembles arousal seeking and impulsivity observed in patients suffering from Tourette syndrome or schizophrenia, neuropsychiatric disorders linked to mutations in Stn2 in humans [10]. These alterations are paired with a partial redistribution of synaptotagmin 1 to the neuronal surface and to active zones while synaptic vesicle endocytosis remains unaffected. A similar coupling between exocytosis and endocytic membrane retrieval is required for the rapid replenishment of release-ready vesicles at active zones at the calyx of Held, a process that depends on the Stn2-associated endocytic scaffold intersectin. Collectively, our data reveal a novel role for endocytic proteins in the modulation of presynaptic plasticity and suggest potential mechanisms by which defective endocytic sorting of SV proteins might cause neurological disorders. References: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Chapman ER, Annu Rev Biochem 77, 615 (2008). Jahn R, Nat Rev Mol Cell Biol 7, 631 (Sep, 2006). Sudhof TC, Science 323, 474 (Jan 23, 2009). Powell CM, Neurobiol Learn Mem 85, 2 (Jan, 2006). Hauck V, Nat Rev Neurosci 12, 127 (Mar, 2011). Opazo F, et al., Traffic 11, 800 (Jun, 2010). Fernandez-Alfonso T, Neuron 51, 179 (Jul 20, 2006). Diril MK, Haucke V, Dev Cell 10, 233 (Feb, 2006). Voglmaier SM, et al., Neuron 51, 71 (Jul 6, 2006). Breedveld GJ, Neurogenetics 11, 417 (Oct, 2010).
CLATHRIN-MEDIATED-ENDOCYTOSIS AND CLATHRIN-DEPENDENT MEMBRANE AND PROTEIN TRAFFICKING; CORE PATHOPHYSIOLOGICAL PROCESSES IN SCHIZOPHRENIA AND BIPOLAR DISORDER? David R. Cotter, Klaus Oliver Schubert, Melanie Föcking Department of Psychiatry, Royal College of Surgeons in Ireland, Smurfit Building, Beaumont Hospital, Dublin, Ireland Clathrin mediated endocytosis (CME) is the best characterized mechanism governing cellular membrane- and protein trafficking. It is critical