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.
Highlights
Synaptic plasticity is central to memory and other adaptive responses of adult neural circuits
Huntington’s disease (HD) is caused by a mutated form of the huntingtin gene and the resulting mutant huntingtin protein (Saudou and Humbert, 2016)
Increasing evidence suggests that cognitive and psychiatric disturbances occur in HD gene carriers and HD mouse models well before classical neuropathology or the onset of motor symptom, suggesting that the initial development of the disease results from a cellular dysfunction rather than a loss of neurons (Lemiere et al, 2004; Solomon et al, 2008)
Summary
Synaptic plasticity is central to memory and other adaptive responses of adult neural circuits. Blocking regulated AMPAR endocytosis and LTD by GluA2-derived peptide (Tat-GluA23Y) prevented the expression and maintenance of D-amphetamine-induced behavioral sensitization (Brebner et al, 2005; Choi et al, 2014), facilitated the extinction of morphine-induced conditioned place preference (Dias et al, 2012), and reduced heroin seeking (Van den Oever et al, 2008) These results suggest a critical role for AMPAR trafficking and AMPAR-mediated plasticity in addictive behavior. The antidepressant tianeptine reversed the corticosterone-induced increase in AMPAR surface diffusion in hippocampal neurons and restored hippocampal LTP in slices from acutely stressed mice (Zhang et al, 2013) This suggests that reversal of AMPAR surface trafficking may contribute to the restoration of hippocampal synaptic plasticity in animal models of stress. The implications of these findings might extend to depression
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