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Key Points The anterior cingulate cortex (ACC) plays an important part in chronic pain states. NMDA-receptor-dependent postsynaptic long-term potentiation (LTP) in the ACC sustains the affective component of the pain state. Kainate-receptor-dependent presynaptic LTP in the ACC contributes to pain-related anxiety. The mechanism for neuropathic pain is linked to the expression of LTP in the ACC. Upregulation of GluN2B-containing NMDA receptors is found in chronic neuropathic pain conditions. Calcium-stimulated adenylyl cyclase 1 is a potential target for future treatment of chronic pain and anxiety. Evidence suggests that activity in the anterior cingulate cortex (ACC) contributes to acute and chronic pain. In this article, Zhuo and colleagues review the different types of synaptic plasticity observed in the ACC and the implications of these forms of plasticity for pain processing. The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety.

Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor–dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.

The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.

A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity.

Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here, we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involves purely an increase in N (LTP N ). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA is activated, results in LTP that is associated with a transient increase in γ (LTP γ ), caused by the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII is necessary and sufficient for LTP N whilst PKA is additionally required for LTP γ . Thus, two mechanistically distinct forms of LTP co-exist at these synapses. Long-term potentiation at hippocampal CA1 synapses can be due to increasing the number and/or single-channel conductance of AMPA receptors. The authors show that PKA and CaMKII are necessary and together sufficient to increase single channel conductance, via insertion of calcium-permeable AMPA receptors.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as 'legal highs' in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many 'legal highs', little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

Key Points Synaptic plasticity is the basis of information storage in the brain. Two of the most studied forms of plasticity, long-term potentiation (LTP) and long-term depression (LTD), involve both glutamate and GABA (γ-aminobutyric acid) receptors, and it is becoming clear that the trafficking of these receptors is an important mechanism in both LTP and LTD. Postsynaptic changes in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) are thought to be important for the expression of LTP. This could involve either the modulation of AMPARs at the synapse or the rapid recruitment of new AMPARs to the synapse. LTD might occur through a mirror mechanism or a distinct process. There is strong evidence that both LTP and LTD involve changes in the number of AMPARs at the synapse. AMPARs can enter or leave the synapse through exocytosis and endocytosis or through lateral diffusion within the membrane. Various protein kinases and phosphatases have been implicated in these processes. In addition, proteins that bind to AMPARs and regulate their function have also been identified. These include N -ethylmaleimide-sensitive factor (NSF) and the PDZ-domain-containing proteins postsynaptic density protein 95 (PSD-95), AMPAR-binding protein (ABP), glutamate-receptor interacting protein (GRIP) and protein interacting with C-kinase (PICK). NMDA ( N -methyl- D -aspartate) receptors (NMDARs) are the most important known trigger for long-term synaptic plasticity. They also show considerable mobility within the membrane and between intracellular and extracellular compartments of cells, although these processes are less well understood than for AMPARs. There is evidence that such trafficking is regulated by activity and could be a mechanism for metaplasticity. Kainate receptors are also important for synaptic plasticity, but little is known about the regulation of their trafficking. Furthermore, the G-protein-coupled metabotropic glutamate receptors (mGluRs) bind to various proteins that could regulate their trafficking in response to activity. Ionotropic GABA A Rs help to regulate the activation of NMDARs, and transmission that is mediated by GABA A Rs is also modulated in response to activity. Their trafficking is likely to be important for synaptic plasticity, and this process shows some similarities to trafficking of AMPARs. Several proteins that bind GABA A Rs and could regulate their trafficking in response to activity have been identified. Metabotropic GABA B Rs are also important for plasticity, and several proteins have been identified that bind these receptors, but their functional importance is unclear. Some common principles are emerging in the regulation of receptor trafficking during synaptic plasticity. These include the stabilization of receptors at the membrane by scaffolding proteins and regulation by kinases and phosphatases. However, specific receptors or subunits are also trafficked by selective mechanisms. Long-term potentiation and long-term depression are processes that have been widely studied to understand the molecular basis of information storage in the brain. Glutamate receptors are required for the induction and expression of these forms of plasticity, and GABA (γ-aminobutyric acid) receptors are involved in their modulation. Recent insights into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for our understanding of the mechanisms of long-term potentiation and long-term depression.

Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely moving mice. We found that selective activation of pyramidal neurons rapidly and acutely reduced nociceptive thresholds and that this effect was occluded in animals made hypersensitive using Freund's Complete Adjuvant (CFA). Conversely, inhibition of ACC pyramidal neurons rapidly and acutely reduced hypersensitivity induced by CFA treatment. A similar analgesic effect was induced by activation of parvalbumin (PV) expressing interneurons, whereas activation of somatostatin (SOM) expressing interneurons had no effect on pain thresholds. Our results provide direct evidence of the pivotal role of ACC excitatory neurons, and their regulation by PV expressing interneurons, in nociception.

The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSC A ) when applied intracellularly. This effect is dependent on postsynaptic Ca 2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca 2+ -permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSC A . These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.

Postnatal glutamatergic principal neuron synapses are typically presumed to express only calcium-impermeable (CI), GluR2-containing AMPARs under physiological conditions. Here, however, we demonstrate that long-term potentiation (LTP) in CA1 hippocampal pyramidal neurons causes rapid incorporation of GluR2-lacking calcium-permeable (CP)-AMPARs: CP-AMPARs are present transiently, being replaced by GluR2-containing AMPARs ∼25 min after LTP induction. Thus, CP-AMPARs are physiologically expressed at CA1 pyramidal cell synapses during LTP, and may be required for LTP consolidation.