AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders

Abstract Over the past two decades, there has been a growing recognition of the physiological importance and pathological implications surrounding the surface diffusion of AMPA receptors (AMPARs) and their diffusional trapping at synapses. AMPAR surface diffusion entails the thermally powered random Brownian lateral movement of these receptors within the plasma membrane, facilitating dynamic exchanges between synaptic and extrasynaptic compartments. This process also enables the activity-dependent diffusional trapping and accumulation of AMPARs at synapses through transient binding to synaptic anchoring slots. Recent research highlights the critical role of synaptic recruitment of AMPARs via diffusional trapping in fundamental neural processes such as the development of the early phases of long-term potentiation (LTP), contextual fear memory, memory consolidation, and sensory input-induced cortical remapping. Furthermore, studies underscore that regulation of AMPAR diffusional trapping is altered across various neurological disease models, including Huntington’s disease (HD), Alzheimer’s disease (AD), and stress-related disorders like depression. Notably, pharmacological interventions aimed at correcting deficits in AMPAR diffusional trapping have demonstrated efficacy in restoring synapse numbers, LTP, and memory functions in these diverse disease models, despite their distinct pathogenic mechanisms. This review provides current insights into the molecular mechanisms underlying the dysregulation of AMPAR diffusional trapping, emphasizing its role as a converging point for multiple pathological signaling pathways. We propose that targeting AMPAR diffusional trapping represents a promising early therapeutic strategy to mitigate synaptic plasticity and memory deficits in a spectrum of brain disorders, encompassing but not limited to HD, AD, and stress-related conditions. This approach underscores an integrated therapeutic target amidst the complexity of these neurodegenerative and neuropsychiatric diseases.