Hongik Hwang1, Matthew J Szucs2, Lei J Ding3, Andrew Allen4, Xiaobai Ren5, Henny Haensgen5, Fan Gao5, Hyewhon Rhim6, Arturo Andrade7, Jen Q Pan4, Steven A Carr2, Rushdy Ahmad2, Weifeng Xu8. 1. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts; Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. Electronic address: hongik@mit.edu. 2. Proteomic Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 3. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. 4. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 5. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts. 6. Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, Republic of Korea. 7. Department of Biological Sciences, University of New Hampshire, Durham, New Hampshire. 8. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts. Electronic address: weifeng_xu@brown.edu.
Abstract
BACKGROUND: Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the postmortem brains of patients with schizophrenia. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown. METHODS: Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phosphorylated targets. An identified candidate was examined with high-throughput planar patch clamp and was validated with pharmacological manipulation. RESULTS: Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels, and ionic transporters, some of which highlighted clusters of schizophrenia- and autism-related genes. Hypophosphorylation of NMDA receptor subunit Grin2A, one significant phosphorylated target, resulted in accelerated decay of NMDA receptor currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDA receptor current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits. CONCLUSIONS: Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.
BACKGROUND: Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the postmortem brains of patients with schizophrenia. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown. METHODS: Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phosphorylated targets. An identified candidate was examined with high-throughput planar patch clamp and was validated with pharmacological manipulation. RESULTS: Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels, and ionic transporters, some of which highlighted clusters of schizophrenia- and autism-related genes. Hypophosphorylation of NMDA receptor subunit Grin2A, one significant phosphorylated target, resulted in accelerated decay of NMDA receptor currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDA receptor current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits. CONCLUSIONS: Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.
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