Probing the role of AMPAR endocytosis and long-term depression in behavioural sensitization: relevance to treatment of brain disorders, including drug addiction

Abstract

Modifying the function of postsynaptic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) is one of the most important mechanisms by which the efficacy of synaptic transmission at excitatory glutamatergic synapses in the mammalian brain is regulated. Traditionally these types of modifications have been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. A large body of evidence accumulated from recent studies strongly suggests that AMPARs, like most integral plasma membrane proteins, are continuously recycled between the plasma membrane and the intracellular compartments via vesicle-mediated plasma membrane insertion and clathrin-dependent endocytosis. Regulation of either receptor insertion or endocytosis results in a rapid change in the number of these receptors expressed on the plasma membrane surface and in the receptor-mediated responses, thereby playing an important role in mediating certain forms of synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD). These studies have significantly advanced our understanding of the molecular mechanisms underlying LTP and LTD, and their potential contributions to learning and memory-related behaviours. Here I provide a brief summary of the current state of knowledge concerning clathrin-mediated AMPAR endocytosis and its relationship to the expression of certain forms of LTD in several brain areas. The potential impact of recent advancements on our efforts to probe the roles of synaptic plasticity in learning and memory-related behaviours, and their relevance to some brain disorders, particularly drug addiction, are also discussed.

Figure 1

Schematic diagram of AMPAR GluR2 subunit showing the proposed membrane topology, along with detailed amino-acid sequences and proposed endocytic motifs of the carboxyl terminal region. MD represents the membrane domain. The putative motif for constitutive AMPAR endocytosis resides within a short stretch of amino acids, which are largely conserved (Conserved) among all four AMPAR subunits (Lin et al., 2000; Ahmadian et al., 2004). The putative motifs for GluR2-dependent regulated AMPAR endocytosis include the AP2-binding motif, which overlaps with the NSF-binding region (Lee et al., 2002), the tyrosine-containing motif (Tyrosine-cluster) (Ahmadian et al., 2004; Hayashi and Huganir, 2004) and PDZ/PICK1-binding motif (Kim et al., 2001; Chung et al., 2003). The sequence of the interference peptide used to probe the role of endocytosis and LTD in behavioural sensitization (Brebner et al., 2005) is also indicated (GluR2_3Y). LTD, long-term depression; NSF, N-ethylmaleimide-sensitive factor.