α2δ-1 regulates synaptic AMPA receptor trafficking and LTP through distinct pre- and postsynaptic functions

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Activity-dependent trafficking of AMPA receptors (AMPARs) is crucial for learning and memory.
• The GluA1 amino-terminal domain (ATD) of AMPARs is vital for synaptic trafficking and long-term potentiation (LTP).
• The GluA1 ATD is positioned in the synaptic cleft, suggesting interactions with extracellular proteins.

Purpose of the Study:

• To identify proteins interacting with the GluA1 ATD.
• To investigate the role of the identified interacting protein, α2δ-1, in synaptic function and memory.
• To elucidate the pre- and postsynaptic functions of α2δ-1 in the hippocampus.

Main Methods:

• Unbiased proteomics to identify GluA1 ATD-interacting proteins.
• Electrophysiological recordings in hippocampal slices to assess synaptic currents and LTP.
• Behavioral testing in rodents to evaluate memory performance after genetic manipulation of α2δ-1.

Main Results:

• The voltage-gated calcium channel (VGCC) auxiliary subunit α2δ-1 was identified as a GluA1 ATD-interacting protein.
• Postsynaptic deletion of α2δ-1 enhanced basal AMPAR currents but did not affect NMDAR currents.
• Presynaptic deletion of α2δ-1 impaired LTP and object location memory, while not affecting basal synaptic transmission.

Conclusions:

• α2δ-1 acts as an extracellular regulator of AMPARs with distinct presynaptic and postsynaptic functions.
• Presynaptic α2δ-1 facilitates LTP and object location memory, while postsynaptic α2δ-1 limits synaptic AMPAR availability.
• These findings expand the understanding of α2δ-1's role in hippocampal function and suggest a potential mechanism for gabapentinoid drug effects.