Linking NMDA Receptor Synaptic Retention to Synaptic Plasticity and Cognition
iScience. 2019-09-01; 19: 927-939
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Franchini L(1), Stanic J(1), Ponzoni L(2), Mellone M(1), Carrano N(1), Musardo S(3), Zianni E(1), Olivero G(4), Marcello E(1), Pittaluga A(4), Sala M(5), Bellone C(3), Racca C(6), Di Luca M(1), Gardoni F(7).
(1)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
(2)CNR Institute of Neuroscience, 20129 Milano, Italy; Fondazione Zardi Gori, 20122 Milano, Italy.
(3)Department of Basic Neurosciences, University of Geneva, 1211 Geneva, Switzerland.
(4)Department of Pharmacy, DiFAR, University of Genova, 16148 Genoa, Italy.
(5)CNR Institute of Neuroscience, 20129 Milano, Italy.
(6)Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
(7)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.
NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used
different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger
downstream signaling events necessary for cognitive behavior.