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

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Synaptic adhesion molecules are critical for synapse development and function.
• The precise mechanisms by which presynaptic adhesion molecules influence postsynaptic NMDAR function are not well understood.
• LAR family receptor tyrosine phosphatases (LAR-RPTPs) are known to regulate synapse development via trans-synaptic adhesion.

Purpose of the Study:

• To investigate whether presynaptic PTPσ, a LAR-RPTP, regulates postsynaptic NMDA receptor (NMDAR) function.
• To elucidate the mechanisms underlying PTPσ-mediated regulation of NMDARs.
• To determine the behavioral relevance of PTPσ-dependent NMDAR regulation.

Main Methods:

• Electrophysiological recordings of NMDAR currents and synaptic plasticity in hippocampal slices.
• Analysis of PTPσ-mutant mice to assess presynaptic protein phosphorylation.
• Behavioral assays for social and reward-related novelty recognition.

Main Results:

• Presynaptic PTPσ enhances postsynaptic NMDAR currents and NMDAR-dependent synaptic plasticity in the hippocampus.
• PTPσ regulation of NMDARs does not rely on trans-synaptic adhesions but involves its cytoplasmic domains.
• PTPσ deficiency leads to increased phosphotyrosine levels of presynaptic proteins, including neurexin-1, and impairs novelty recognition.

Conclusions:

• Presynaptic PTPσ modulates postsynaptic NMDAR function through both trans-synaptic and adhesion-independent mechanisms.
• The tyrosine phosphatase activity of PTPσ's cytoplasmic domains is critical for regulating presynaptic protein phosphorylation.
• PTPσ-mediated NMDAR regulation plays a vital role in social and reward-driven novelty recognition behaviors.