Neurogranin, Encoded by the Schizophrenia Risk gene RGN, bidirectionally modulates synaptic plasticity via calmodulin-dependent regulation of the neuronal phosphoproteome

Title
Neurogranin, Encoded by the Schizophrenia Risk gene RGN, bidirectionally modulates synaptic plasticity via calmodulin-dependent regulation of the neuronal phosphoproteome
Authors
임혜원황홍익Matthew J. SzucsLei J. DingAndrew AllenXiaobai RenHenny HaensgenFan GaoArturo AndradeJen Q. PanSteven A. CarrRushdy AhmadWeifeng Xu
Issue Date
2021-02
Publisher
Biological psychiatry
Citation
VOL 89, NO 3-269
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 cog
URI
http://pubs.kist.re.kr/handle/201004/72162
ISSN
0006-3223
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