Presynaptic PTPσ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms

Abstract

Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTPσ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-synaptic adhesions of PTPσ, suggesting that the cytoplasmic domains of PTPσ, known to have tyrosine phosphatase activity and mediate protein-protein interactions, are important. In line with this, phosphotyrosine levels of presynaptic proteins, including neurexin-1, are strongly increased in PTPσ-mutant mice. Behaviorally, PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition. These results suggest that presynaptic PTPσ regulates postsynaptic NMDAR function through trans-synaptic and direct adhesion-independent mechanisms and novelty recognition in social and reward contexts.

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

“…Previous KO mouse studies have revealed the importance of LAR-RPTPs for synaptic and cognitive function. Specifically, PTPσ KO decreases presynaptic release probability and NMDAR-dependent LTP in the hippocampal Schaffer-CA1 synapses and abnormally enhances novel object recognition (Horn et al, 2012 ; Han et al, 2020a ; Kim et al, 2020 ). In contrast, a previous study by Uetani et al ( 2000 ) showed that PTPδ KO increases release probability and LTP in the same type of synapses and impairs spatial learning and memory.…”

Perineuronal net receptor PTPσ regulates retention of memories

“…PTPσ deficiency also increases frequency but reduces efficiency of excitatory postsynaptic currents (Horn et al, 2012;Han et al, 2020) and impairs long-term potentiation (LTP) (Horn et al, 2012). LTP deficits were also observed when PTPσ knockdown was restricted to excitatory cortical and hippocampal neurons (Kim et al, 2020). Similarly, overexpression TRKB in pyramidal neurons, which increases TRKB phosphorylation and signaling through PLCγ1, also impairs LTP (Koponen et al, 2004).…”

“…Similarly, overexpression TRKB in pyramidal neurons, which increases TRKB phosphorylation and signaling through PLCγ1, also impairs LTP (Koponen et al, 2004). Interestingly, Kim et al showed that presynaptic PTPσ deficiency selectively impairs NMDA-dependent postsynaptic currents, and it happens through a mechanism independent of PTPσ trans-synaptic adhesion, suggesting further involvement of PTPσ cytoplasmic phosphatase domains in this process (Kim et al, 2020). Even though direct relationship between LTP and memory remains to be a subject to debate (Stevens, 1998;Nicoll, 2017), NMDA-dependent LTP is known to be critical for normal memory performance, and disturbances in this pathway impair memory function (Nakazawa et al, 2004;Li and Tsien, 2009;Morris, 2013;Nabavi et al, 2014).…”

Feature Matching Synchronized Reasoning from Energy-Based Memory Network for Intelligent Data Management in Cloud Computing Data Center

“…For the brain to operate properly, the synapses that make up the neural circuits must work well [21]. The major adhesion protein PTPσ is found in specific neural circuits in the hippocampus and is known to mediate memory and regulate function by helping localize and stabilize NMDA receptors [22]. Synapses can continuously change their structure and function according to their activities and play an important role in memory formation [23].…”