Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

Abstract

AMPA receptors (AMPARs) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission throughout the brain. Changes in the properties and postsynaptic abundance of AMPARs are pivotal mechanisms in synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. A wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders, despite their extremely diverse etiology, pathogenesis and symptoms, exhibit brain region-specific and AMPAR subunit-specific aberrations in synaptic transmission or plasticity. These include abnormally enhanced or reduced AMPAR-mediated synaptic transmission or plasticity. Bidirectional reversal of these changes by targeting AMPAR subunits or trafficking ameliorates drug-seeking behavior, chronic pain, epileptic seizures, or cognitive deficits. This indicates that bidirectional dysregulation of AMPAR-mediated synaptic transmission or plasticity may contribute to the expression of many brain disorders and therefore serve as a therapeutic target. Here, we provide a synopsis of bidirectional AMPAR dysregulation in animal models of brain disorders and review the preclinical evidence on the therapeutic targeting of AMPARs.

Crosstalk between biochemical signaling and trafficking determines AMPAR dynamics in synaptic plasticity

“…Additionally, many neurological disorders and diseases include a component of AMPAR dysregulation, Figure 8b. For example, Huntington's disease involves a disruption in the binding between AMPAR and scaffolding molecules such as PSD-95; both Alzheimer's Disease and Parkinson's Disease related dementia involve an increase in AMPAR endocytosis in response to Aβ oligomers, while Parkinson's Disease also involves an impairment in scaffold binding and AMPAR endocytosis; and mental stress is believed to cause increases in AMPAR lateral diffusion [86]. Therefore, it is clear that the regulation and dynamics of AMPAR have significant neurological consequences.…”

AMPA Receptors: A Key Piece in the Puzzle of Memory Retrieval

“…Further comprehension on AMPAR-mediated plasticity mechanisms will shed light on more selective potential targets ( Zhang and Bramham, 2020 ) regarding memory retrieval deficits associated with neurological diseases.…”

Arc/Arg3.1 function in long‐term synaptic plasticity: Emerging mechanisms and unresolved issues

“…AMPARs constitutively cycle between an intracellular pool and the neuronal surface by exocytosis/endocytosis, and exchange between synaptic and extrasynaptic compartments in the membrane by lateral diffusion. The regulated recruitment of AMPARs to and from the postsynaptic membrane underlies enhanced and decreased synaptic transmission in NMDAR‐dependent LTP and LTD, respectively (Zhang & Bramham, 2020). mGluR‐dependent LTD is also expressed as a decrease in postsynaptic AMPAR number (Jakkamsetti et al., 2013; Park et al., 2008; Waung et al., 2008; Wilkerson et al., 2018).…”