Both theoretical and experimental work have suggested that central neurons compensate for changes in excitatory synaptic input in order to maintain a relatively constant output. We report here that inhibition of excitatory synaptic transmission in cultured spinal neurons leads to an increase in mEPSC amplitudes, accompanied by an equivalent increase in the accumulation of AMPA receptors at synapses. Conversely, increasing excitatory synaptic activity leads to a decrease in synaptic AMPA receptors and a decline in mEPSC amplitude. The time course of this synaptic remodeling is slow, similar to the metabolic half-life of neuronal AMPA receptors. Moreover, inhibiting excitatory synaptic transmission significantly prolongs the half-life of the AMPA receptor subunit GluR1, suggesting that synaptic activity modulates the size of the mEPSC by regulating the turnover of postsynaptic AMPA receptors.
Non-NMDA glutamate receptor subunits of the AMPA-preferring subfamily combine to form ion channels with heterogeneous functional properties. We have investigated the effects of RNA editing at the Q/R site, splice variation of the "flip/flop" cassette, and multimeric subunit assembly on the single-channel conductance and kinetic properties of the recombinant AMPA receptors formed from GluR2 and GluR4 expressed in HEK 293 cells. We found that AMPA receptor single-channel conductance was dependent on the Q/R site editing state of the subunits comprising the channel. Calcium-permeable (unedited) channels had resolvable single-channel events with main conductance states of 7-8 pS, whereas fully edited GluR2 channels had very low conductances of approximately 300 fS (estimated from noise analysis). Additionally, the flip splice variant of GluR4 conferred agonist-dependent conductance properties reminiscent of those found for a subset of AMPA receptors in cultured cerebellar granule cells. These results provide a description of the single-channel properties of certain recombinant AMPA receptors and suggest that the single-channel conductance may be determined by the expression of edited GluR2 subunits in neurons.
1. Whole‐cell recordings were made from cerebellar granule cells cultured in high‐K+ medium to induce expression of Ca(2+)‐permeable AMPA receptors. Current‐voltage (I‐V) plots of agonist‐evoked responses showed varying degrees of inward rectification, but became linear within 5‐10 min. 2. Recombinant Ca(2+)‐permeable kainate receptors, composed of GluR6(Q)/KA‐2 subunits, exhibited rectifying whole‐cell I‐V plots that became linear in outside‐out patches. 3. Loss of rectification in granule cells was prevented by including 100 microM spermine in the pipette; the degree of rectification was then correlated with Ca2+ permeability. 4. Spermine also prevented loss of rectification in patches containing GluR6(Q)/KA‐2 receptors (IC50, 1.7 microM). 5. We suggest that spermine, or a similar cellular constituent, may act as a cytoplasmic factor conferring inward rectification on Ca(2+)‐permeable non‐NMDA receptors, and that ‘washout’ of this factor underlies the observed loss of rectification.
Glutamate receptors mediate the majority of rapid excitatory synaptic transmission in the central nervous system (CNS) and play important roles in synaptic plasticity and neuronal development. Recently, protein-protein interactions with the C-terminal domain of glutamate receptor subunits have been shown to be involved in the modulation of receptor function and clustering at excitatory synapses. In this paper, we have found that the N-ethylmaleimide-sensitive factor (NSF), a protein involved in membrane fusion events, specifically interacts with the C terminus of the GluR2 and GluR4c subunits of AMPA receptors in vitro and in vivo. Moreover, intracellular perfusion of neurons with a synthetic peptide that competes with the interaction of NSF and AMPA receptor subunits rapidly decreases the amplitude of miniature excitatory postsynaptic currents (mEPSCs), suggesting that NSF regulates AMPA receptor function.
The transient period of memory instability that can be triggered when memories are retrieved under certain conditions offers an opportunity to modify the maladaptive memories at the heart of substance use disorders (SUDs). However, very well-learned memories (such as those in excessive drinking and alcohol use disorders) are resistant to destabilisation when retrieved or may not destabilise at all. Memory retrieval and intervention procedures that reliably destabilise and update maladaptive motivational memories may help to improve the long-term treatment of SUDs. In 59 hazardous drinkers, we tested a novel retrieval procedure for destabilising well-learned cue-drinking memory networks that maximises prediction error (PE) via guided expectancy violation during retrieval of these memories. This was compared with a retrieval procedure without PE and no-retrieval controls. We subsequently counterconditioned alcohol cues with disgusting tastes and images in all groups and assessed responding to alcohol stimuli 1 week later. Counterconditioning following PE retrieval produced generalised reductions in oculomotor attentional bias, explicit valuation and outcome expectancies in response to alcohol cues 1 week after intervention, evidence of updating of distributed motivational drinking memory networks. These findings demonstrate that well-learned cue-drinking memories can be destabilised and that learning history need not constrain memory destabilisation if PE is maximised at retrieval. Broad rewriting of diverse aspects of maladaptive memory by counterconditioning is achievable following this procedure. The procedure described may provide a platform for the development of novel memory-modifying interventions for SUDs.
These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.
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