Synaptic AMPA Receptor Plasticity and Behavior

The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors (AMPARs), respectively. We here present an overview of studies that have used animal models to show that such AMPAR trafficking underlies several experience-driven phenomena—from neuronal circuit formation to the modification of behavior. We argue that monitoring and manipulating synaptic AMPAR trafficking represents an attractive means to study cognitive function and dysfunction in animal models

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators

N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2's M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation

AMPA receptor trafficking and long-term potentiation

Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms have been the subject of considerable scrutiny over the past few decades. I review studies from our laboratory that support a critical role for AMPA receptor trafficking in LTP and experience-dependent plasticity

Multiple Mechanisms for the Potentiation of AMPA Receptor- Mediated Transmission by -Ca2 /Calmodulin-Dependent Protein Kinase II

Some forms of activity-dependent synaptic potentiation require the activation of postsynaptic Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Activation of CaMKII has been shown to phosphorylate the glutamate receptor 1 subunit of the AMPA receptor (AMPAR), thereby affecting some of the properties of the receptor. Here, a recombinant, constitutively active form of alphaCaMKII tagged with the fluorescent marker green fluorescent protein (GFP) [alphaCaMKII(1-290)-enhanced GFP (EGFP)] was expressed in CA1 pyramidal neurons from hippocampal slices. The changes in glutamatergic transmission onto these cells were analyzed. AMPA but not NMDA receptor-mediated EPSCs were specifically potentiated in infected compared with nearby noninfected neurons. This potentiation was associated with a reduction in the proportion of synapses devoid of AMPARs. In addition, expression of alphaCaMKII(1-290)-EGFP increased the quantal size of AMPAR-mediated responses. This effect reflected, at least in part, an increased unitary conductance of the channels underlying the EPSCs. These results reveal that several key features of long-term potentiation of hippocampal glutamatergic synapses are reproduced by the sole activity of alphaCaMKII.This work was supported by the Human Frontier Science Program Organization (J.C.P.) and by the Mathers Foundation and the National Institutes of Health (R.M.). We thank Nancy Dawkins-Pisani for technical assistance, Norbert Ankri for providing event detection and analysis software, and Yasunori Hayashi and Richard Miles for critical reading of this manuscript.Peer reviewe

Elevated PSD-95 Blocks Ion-flux Independent LTD: A Potential New Role for PSD-95 in Synaptic Plasticity

We recently demonstrated that NMDA receptors (NMDARs) are capable of ion-flux independent signaling through conformational change in the NMDAR intracellular domain resulting in long-term depression of synaptic transmission (LTD). Here we show that PSD-95 overexpression blocks agonist induced conformational movement in the NMDAR intracellular domain as well as LTD that is NMDAR-dependent and ion-flux independent. Interestingly, previous studies indicate that overexpressed PSD-95 does not block NMDAR-dependent LTD. These data support a model where ion-flux independent LTD is predominant in young animals, which have synapses with low amounts of PSD-95, whereas only ion flux dependent LTD occurs at more mature synapses, which have more PSD-95 that would block ion-flux independent LTD. These results may reconcile different findings regarding ion-flux independent LTD

A molecular mechanism for the regulated synaptic delivery of GluR4-containing AMPA receptors

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A PKA-mediated mechanism for the regulaed synaptic delivery of GluR4-containing AMPA receptors.

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Fluctuations in intracellular calcium responses to action potentials in single en passage presynaptic boutons of layer V neurons in neocortical slices

The release of neurotransmitter from a nerve terminal on invasion by an action potential shows large trial-to-trial fluctuations. The factors contributing to this variability have not been elucidated clearly. Here, simultaneous patch-clamp and optical measurements from layer V neocortical pyramidal neurons have been used to assess the extent to which the fluctuations in transmitter release may be caused by variability in calcium rise in presynaptic structures. Boutons on axon collaterals were visualized and increases in intracellular calcium, assessed by Fura-2, were observed in response to single action potentials. In some boutons, calcium responses showed trial-to-trial variability and occasional apparent failures despite the faithful conduction of the action potential. These results suggest that a factor contributing to the fluctuation in transmitter release may be the variability with which depolarization of a presynaptic bouton produces an increase in intrabouton calcium

Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part I: trans-Golgi network-derived organelles undergo regulated exocytosis

Exocytosis is a widely observed cellular mechanism for delivering transmembrane proteins to the cell surface and releasing signaling molecules into the extracellular space. Calciumevoked exocytosis, traditionally thought to be restricted to presynaptic specializations in neurons, has been described recently in many cells. Here, calcium-evoked dendritic exocytosis (CEDE) is visualized in living cultured hippocampal neurons. Organelles that undergo CEDE are in somata, dendrites, and perisynaptic regions, identified by using immunocytochemistry and correlative light and electron microscopy. CEDE is regulated developmentally: neurons �9din vitro do not show CEDE. In addition, CEDE is blocked by tetanus toxin, an inhibitor of regulated exocytosis, and nocodazole, an inhibitor of microtubule polymerization. Organelles that undergo CEDE often are found on the base of spines, putative sites of synapti

PKA-mediated mechanism for the regulated synaptic delivery of GluR4-containing AMPA receptors

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