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    • Here we provide evidence that NO

    2024-03-07

    Here, we provide evidence that NO contributes to changes in synaptic strength, but also offer an explanation as to why previous attempts to link NO to LTP have often failed. Our results describe a model by which cycling AMPARs, held in intracellular pools, are rapidly delivered to the membrane surface by a NO-mediated activation of NSF. This work is consistent with PICK1 suppressing the availability of select AMPARs for surface expression, disrupted only when S-nitrosylated NSF chaperones receptors towards the plasma membrane. This PICK1-regulated process may likely underlie different forms of potentiation.
    Acknowledgements
    Introduction Glutamate mediates the majority of excitatory neurotransmission in the SC 144 synthesis by activating the AMPA-subtype of ionotropic glutamate receptors (iGluRs). Consequently, many studies of synaptic plasticity have focused on the mechanism of local changes in the composition and number of postsynaptic AMPA receptors (AMPARs), with particular focus on changes that underlie the phenomena of long-term potentiation (LTP) and long-term depression (LTD) (Anggono and Huganir, 2012, Kerchner and Nicoll, 2008, Kessels and Malinow, 2009, Malenka and Bear, 2004). These potentiation protocols cause local, synapse-specific changes in postsynaptic receptors and thus modify the strength of neurotransmission. Additionally, information processing by neural circuits is dependent on maintaining an optimal strength of synaptic inputs in the face of constant perturbations. Thus, postsynaptic receptor numbers are tightly constrained by homeostatic mechanisms (Davis, 2013, Turrigiano, 2008). However, the molecular mechanisms that maintain the optimal number of AMPARs at a given synapse are still not well understood. Even less understood is the logistical problem of maintaining AMPAR numbers at the hundreds to thousands of independently functioning synapses that are distributed along dendritic branches that can extend hundreds of microns from the neuronal cell body. We approached the question of how AMPARs are maintained at synapses using an experimental design that allowed us to integrate in vivo cell biological and electrophysiological studies in C. elegans. A subset of the 302 neurons in the C. elegans nervous system communicate by the synaptic release of glutamate and these neurons contribute to specific behaviors (de Bono and Maricq, 2005). In particular, interneurons that participate in the control of worm movement and avoidance responses express the GLR-1 AMPAR signaling complex, which is composed of multiple receptor and auxiliary subunits, and is responsible for fast postsynaptic glutamate-gated current. In mutants where a component of the complex has been disrupted, such as the GLR-1 subunit, the ratio of forward to backward movement is altered, thus disrupting foraging behavior (de Bono and Maricq, 2005, Zheng et al., 1999) as well as the avoidance response to tactile and osmotic stimuli (Hart et al., 1995, Maricq et al., 1995). We identified many of the molecular components of the GLR-1 signaling complex, including the GLR-2 AMPAR subunit, and the auxiliary proteins SOL-1, SOL-2, and STG-2, and determined how they contribute to postsynaptic function and the control of behavior (Brockie et al., 2001, Brockie et al., 2013, Mellem et al., 2002, Walker et al., 2006b, Wang et al., 2008, Wang et al., 2012, Zheng et al., 2004, Zheng et al., 2006). Recently, we demonstrated that evolutionarily conserved kinesin-1 microtubule-dependent motors mediate the delivery and removal of postsynaptic AMPARs. In unc-116 (KIF5) mutants, the active transport of GLR-1 is abolished, and the peak amplitude of glutamate-gated current greatly reduced (Hoerndli et al., 2013). These findings have important implications for synaptic function and plasticity because kinesin motors, and their GLR-1 cargo, are distributed along the length of a neuronal process and can rapidly repopulate synapses with AMPARs (Hoerndli et al., 2013). Indeed, each synapse is at most only a few seconds removed from motors transporting AMPAR cargo, raising the question of how neurons regulate the motor-driven delivery and removal of synaptic receptors.