Hwang, Hongik Szucs, Matthew J. Ding, Lei J. Allen, Andrew Ren, Xiaobai Haensgen, Henny Gao, Fan Rhim, Hyewhon Andrade, Arturo Pan, Jen Q. Carr, Steven A. Ahmad, Rushdy Xu, Weifeng 2024-01-19T15:32:06Z 2024-01-19T15:32:06Z 2021-09-02 2021-02 0006-3223 https://pubs.kist.re.kr/handle/201004/117463 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. English Elsevier BV Neurogranin, Encoded by the Schizophrenia Risk Gene NRGN, Bidirectionally Modulates Synaptic Plasticity via Calmodulin-Dependent Regulation of the Neuronal Phosphoproteome Article 10.1016/j.biopsych.2020.07.014 1 Biological Psychiatry, v.89, no.3, pp.256 - 269 Biological Psychiatry 89 3 256 269 N scie scopus 000603473100011 2-s2.0-85092090912 Neurosciences Psychiatry Neurosciences & Neurology Psychiatry Article LONG-TERM POTENTIATION PROTEIN-KINASE-II GENOME-WIDE ASSOCIATION TETANIC STIMULATION SIGNAL-TRANSDUCTION COMMON VARIANTS BINDING PHOSPHORYLATION EXPRESSION LTP