Linking NMDA Receptor Synaptic Retention to Synaptic Plasticity and Cognition

Abstract

SummaryNMDA 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.

Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory

“…However, other studies described an impairment in a fear-conditioning task both in a GluN2A knockdown model (de Solis et al, 2015) and after blocking GluN2A-NMDAR in the amygdala (Dalton et al, 2012). Moreover, it has been described that a single training session is sufficient to alter GluN2A expression during memory consolidation (Cercato et al, 2017;Baez et al, 2018;Franchini et al, 2019). In the present study, we analyzed recognition and context-fear learning and memory in two different paradigms in order to evaluate the hippocampal role of GluN2A in each task.…”

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

“…Moreover, Neto1 knockout mice were impaired in a displaced object recognition task, but not in a novel object recognition task, suggesting a specific deficit in a hippocampal dependent test [118]. Similarly, Franchini et al found that mice treated with a cell-permeable peptide that interferes with Rph3A-mediated GluN2A synaptic delivery also display memory defects in the object displacement task [125].…”

“…Similarly, Franchini et al found also in primary hippocampal cultures a synaptic increase of GluN2A driven by chemically induced LTP protocol, with a concurrent increase of its CTD-binding partner Rph3A (see Figure 1). Interestingly, interfering with GluN2A/Rph3A interaction prevents the synaptic increase of GluN2A levels [125].…”

“…Remarkably Rhp3A silencing in vitro blocks LTP induction. Interfering with Rph3A/GluN2A interaction produces the same effect and in vivo induces a strong memory deficit [125]. Other important interactors of GluN2A CTD that modulate its function in synaptic plasticity are protein kinases.…”

The depolarization-evoked, Ca2+-dependent release of exosomes from mouse cortical nerve endings: new insights into synaptic transmission.

“…The exosomal lysates were particularly enriched in TSG101, CD63 and CD9 proteins when compared to the synaptosomal ones, while flotillin-1 was strongly detected also in synaptosomes. We then analysed the presence of the following synaptosomal markers: synaptotagmin-1, a synaptic vesicles membrane protein; syntaxin-1a, which is located in presynaptic plasma membranes; postsynaptic density protein 95 (PSD-95), a membrane protein having a postsynaptic localization (Bonanno et al, 2005;Bonfiglio et al, 2019;Franchini et al, 2019). Synaptosomal lysates showed a clear immunoreactivity for all the three proteins (synaptotagmin-1, 60 kDa; syntaxin-1a, 36 kDa; PSD-95, 95 kDa), while the exosomal lysates were immunopositive for syntaxin-1a, although to a lower extent than the synaptosomal lysates, but lack the synaptotagmin-1 and PSD-95 signals (Figure 4).…”