Incubation of cocaine seeking following brief cocaine experience in mice is enhanced by mGluR1 blockade.

The incubation of cocaine craving describes the time-dependent augmentation of cue-induced cocaine seeking during withdrawal from prolonged cocaine self-administration and requires time-dependent changes in neuroplasticity at the level of glutamatergic synapses in the nucleus accumbens (NAc). In contrast to most studies that use multiple cocaine-cue conditioning sessions, the present study tested mice with limited cocaine experience (i.e., a single conditioning session) in the incubation of cue-mediated cocaine seeking and its associated changes in the glutamate system. Mice that self-administered cocaine during a single session exhibited a time-dependent increase in their response for the drug-associated cue as compared to mice that self-administered saline. This behavior was associated with changes in AMPA and NMDA receptor binding characteristics. Furthermore, Group I metabotropic glutamate receptor (mGluR1) mRNA levels were altered in several brain regions, including the NAc. Because of the pivotal role of mGluR1 in the control of cocaine-induced plasticity, we investigated the role of mGluR1 in the formation of drug cue-mediated cocaine seeking. After prolonged withdrawal, mice in which an mGluR1 antagonist was administered following cocaine self-administration displayed increased cocaine seeking compared to vehicle-treated mice. These results suggest that limited cocaine experience is sufficient to induce neurobiological changes that enable an initially neutral cue to acquire motivational value that increases over time, an effect that likely involves glutamate signaling through mGluR1.

Rapidly repeated visual stimulation induces long-term potentiation of VEPs and increased content of membrane AMPA and NMDA receptors in the V1 cortex of cats.

Studies report that rapidly repeated sensory stimulation can evoke LTP-like improvement of neural response in the sensory cortex. Whether this neural response potentiation is similar to the classic LTP induced by presynaptic electrical stimulation remains unclear. This study examined the effects of repeated high-frequency (9 Hz) versus low-frequency (1 Hz) visual stimulation on visually-evoked field potentials (VEPs) and the membrane protein content of AMPA / NMDA receptors in the primary visual cortex (V1) of cats. The results showed that repeated high-frequency visual stimulation (HFS) caused a long-term improvement in peak-to-peak amplitude of V1-cortical VEPs in response to visual stimuli at HFS-stimulated orientation (SO: 90°) and non-stimulated orientation (NSO: 180°), but the effect exhibited variations depending on stimulus orientation: the amplitude increase of VEPs in response to visual stimuli at SO was larger, reached a maximum earlier and lasted longer than at NSO. By contrast, repeated low-frequency visual stimulation (LFS) had not significantly affected the amplitude of V1-cortical VEPs in response to visual stimuli at both SO and NSO. Furthermore, the membrane protein content of the key subunit GluA1 of AMPA receptors and main subunit NR1 of AMPA receptors in V1 cortex was significantly increased after HFS but not LFS when compared with that of control cats. Taken together, these results indicate that HFS can induce LTP-like improvement of VEPs and an increase in membrane protein of AMPA and NMDA receptors in the V1 cortex of cats, which is similar to but less specific to stimulus orientation than the classic LTP.

Contribution of AMPA and NMDA receptors in the spontaneous firing patterns of single neurons in autaptic culture.

Single neurons in an autaptic culture exhibit various types of firing pattern with different firing durations and rhythms. However, a neuron with autapses has often been modeled as an oscillator providing a monotonic firing pattern with a constant periodicity because of the lack of a mathematical model. In the work described in this study, we use computational simulation and whole-cell patch-clamp recording to elucidate and model the mechanism by which such neurons generate various firing pattens. In the computational simulation, three types of spontaneous firing pattern, i.e., short, long-lasting, and periodic burst firing patterns are realized by changing the combination ratio of N-methyl-d-aspartate (NMDA) to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) conductance. These three types of firing patterns are also observed in the experiments where neurons are cultured in isolation on micropatterned substrates. Using the AMPA and NMDA current models, we discuss that, in principle, autapses can regulate rhythmicity and information selection in neuronal networks.

A cortical model with multi-layers to study visual attentional modulation of neurons at the synaptic level.

Visual attention is a selective process of visual information and improves perceptual performance by modulating activities of neurons in the visual system. It has been reported that attention increased firing rates of neurons, reduced their response variability and improved reliability of coding relevant stimuli. Recent neurophysiological studies demonstrated that attention also enhanced the synaptic efficacy between neurons mediated through NMDA and AMPA receptors. Majority of computational models of attention usually are based on firing rates, which cannot explain attentional modulations observed at the synaptic level. To understand mechanisms of attentional modulations at the synaptic level, we proposed a neural network consisting of three layers, corresponding to three different brain regions. Each layer has excitatory and inhibitory neurons. Each neuron was modeled by the Hodgkin-Huxley model. The connections between neurons were through excitatory AMPA and NMDA receptors, as well as inhibitory GABAA receptors. Since the binding process of neurotransmitters with receptors is stochastic in the synapse, it is hypothesized that attention could reduce the variation of the stochastic binding process and increase the fraction of bound receptors in the model. We investigated how attention modulated neurons' responses at the synaptic level on the basis of this hypothesis. Simulated results demonstrated that attention increased firing rates of neurons and reduced their response variability. The attention-induced effects were stronger in higher regions compared to those in lower regions, and stronger for inhibitory neurons than for excitatory neurons. In addition, AMPA receptor antagonist (CNQX) impaired attention-induced modulations on neurons' responses, while NMDA receptor antagonist (APV) did not. These results suggest that attention may modulate neuronal activity at the synaptic level.

Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated. We review the current state of computational studies on two major members of the family, AMPA and NMDA receptors, with focus on molecular simulations and elastic network model analyses that have provided insights into the coupled movements of extracellular and transmembrane domains. We describe the newly emerging mechanisms of activation, allosteric signaling and desensitization, as mainly a selective triggering of pre-existing soft motions, as deduced from computational models and analyses that leverage structural data on intact AMPA and NMDA receptors in different states.

Local Somatodendritic Translation and Hyperphosphorylation of Tau Protein Triggered by AMPA and NMDA Receptor Stimulation.

Tau is a major component of the neurofibrillary tangles (NFT) that represent a pathological hallmark of Alzheimer's disease (AD). Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegeneration in AD. Here, we show the presence of tau mRNA in a dendritic ribonucleoprotein (RNP) complex that includes Ca2+-calmodulin dependent protein kinase (CaMK)IIα mRNA and that is translated locally in response to glutamate stimulation. Further, we show that Tau mRNA is a component of mRNP granules that contain RNA-binding proteins, and that it interacts with Myosin Va, a postsynaptic motor protein; these findings suggest that tau mRNA is transported into dendritic spines. We also report that tau mRNA localized in the somato-dendritic component of primary hippocampal cells and that a sub-toxic concentration of glutamate enhances local translation and hyperphosphorylation of tau, effects that are blocked by the gluatamatergic antagonists MK801 and NBQX. These data thus demonstrate that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) stimulation redistributes tau to the somato-dendritic region of neurons where it may trigger neurodegeneration.

Cooperative Dynamics of Intact AMPA and NMDA Glutamate Receptors: Similarities and Subfamily-Specific Differences.

Ionotropic glutamate receptors (iGluRs) are tetrameric ion channels that mediate excitatory neurotransmission. Recent structures of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors permit a comparative analysis of whole-receptor dynamics for the first time. Despite substantial differences in the packing of their two-domain extracellular region, the two iGluRs share similar dynamics, elucidated by elastic network models. Motions accessible to either structure enable conformational interconversion, such as compression of the AMPA receptor toward the more tightly packed NMDA receptor conformation, which has been linked to allosteric regulation. Pivoting motions coupled to concerted rotations of the transmembrane ion channel are prominent between dimers of distal N-terminal domains in the loosely packed AMPA receptor. The occurrence and functional relevance of these motions is verified by cross-linking experiments designed to probe the computationally predicted distance changes. Together with the identification of hotspot residues acting as mediators of allosteric communication, our data provide a glimpse into the dynamic spectrum of iGluRs.