A Small Interfering Peptide Potentiates AMPA Receptor Diffusional Trapping and Prevents Social-Isolation-Induced Forgetting of Fear Memory

Regulation and dysregulation of AMPA receptor (AMPAR) diffusional trapping at synapses are critical for synaptic efficacy and are implicated in various neurological and neuropsychiatric disorders. However, the limited availability of reliable tools to modulate this process hinders our ability to explore its role in both physiological conditions and disease, as well as in drug development. In this study, we designed and characterized a 21-amino-acid trans-activator of transcription (TAT)-fused peptide that mimics the binding region of the transmembrane AMPAR regulatory proteins (TARPs) C-tail to the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) N-lobe. Acute intrahippocampal infusion of this peptide enhanced perforant path-evoked synaptic transmission in the rat dentate gyrus (DG) in vivo, likely by strengthening the interaction between TARP and postsynaptic density protein 95 (PSD-95), a mechanism crucial for the synaptic anchoring of AMPARs. Additionally, the peptide also slowed AMPAR lateral diffusion and blocked KCl-induced AMPAR endocytosis, likely by enhancing the diffusional trapping of AMPARs at the synapse. Remarkably, a 7-day peptide infusion prevented social-isolation-induced forgetting of fear memory. Our findings suggest that targeting AMPAR diffusional trapping, particularly through disrupting the TARP-Arc N-lobe interaction, could hold promise as a therapeutic approach for neurological and neuropsychiatric disorders associated with impaired AMPAR synaptic retention.