Abstract
Glutamatergic synapses play critical roles in brain functions and diseases. Long-term potentiation (LTP) is a most effective cellular model for investigating the synaptic changes that underlie learning as well as brain disease – although different molecular mechanisms are likely involved in LTP in physiological and pathological conditions. In the case of learning, N-methyl-D-aspartate (NMDA) receptor is known to be important for triggering learning-related plasticity; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors are thought to be important for the expression of synaptic changes. In this review, I will examine recent evidence on the novel roles of NMDA receptors, in particular NR2B subunit-containing NMDA receptors in learning and chronic pain. A positive feedback control of NR2B receptor subunit is proposed to explain cortical sensitization involved in chronic pain, but not learning and memory.
Highlights
The NMDA receptor acts as an activity-dependent coincidence detector in the central nervous system (CNS)
By focusing on physiological and pathological functions, I will examine previous and recent evidence for long-term plastic changes of NMDA receptor NR2B subunit in the central sensory and 'learning' synapses, as well as the molecular machinery that may contribute to NMDA receptor NR2B subunit trafficking and postsynaptic insertion
Upregulation of NMDA receptor NR2B subunit functions in chronic pain In NMDA receptor NR2B subunit genetically overexpression mice, we found that chronic pain – but not acute or physiological pain – was selectively enhanced [30,42], providing the first genetic evidence that forebrain NMDA NR2B receptor is critical for chronic pain
Summary
The NMDA receptor acts as an activity-dependent coincidence detector in the central nervous system (CNS). In a recent study using gene knockout of KA receptor subtype 6 (KA GluR6) mice, the pairing induced LTP was reduced or blocked in the ACC and amygdala, suggesting that KA receptor may contribute to synaptic potentiation [23]. In the behavioral allodynia test, microinjection into the ACC or systemic administration of NMDA NR2B receptor with selective antagonists inhibited behavioral responses to peripheral inflammation [17] These results are consistent with genetic studies that mice with NMDA receptor NR2B subunit forebrain overexpression selectively enhanced inflammation-related persistent pain without significant changes in acute pain [43]. The antiallodynic effects of NMDA NR2B receptor antagonists have been reported in other animal models of chronic pain We believe that these findings provide direct evidence that NMDA NR2B receptors undergo long-term plastic changes in the brain after injury. We are just beginning to understand how central synapses may undergo plastic changes during learning or after peripheral tissue injury, understanding basic mechanisms for such long-term plasticity may help us to design better medicines for treating memory loss and chronic pain
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