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AMPA‐type glutamate receptors (AMPARs) are key molecules of neuronal communication in our brain. The discovery of AMPAR auxiliary subunits, such as proteins of the TARP, CKAMP and CNIH families, fundamentally changed our understanding of how AMPAR function is regulated. Auxiliary subunits control almost all aspects of AMPAR function in the brain. They influence AMPAR assembly, composition, structure, trafficking, subcellular localization and gating. This influence has important implications for synapse function. In the present review, we first discuss how auxiliary subunits affect the strength of synapses by modulating number and localization of AMPARs in synapses as well as their glutamate affinity, conductance and peak open probability. Next we explain how the presence of auxiliary subunits alters temporal precision and integrative properties of synapses by influencing gating kinetics of the receptors. Auxiliary subunits of the TARP and CKAMP family modulate synaptic short‐term plasticity by increasing anchoring of AMPARs in synapses and by altering their desensitization kinetics. We then describe how auxiliary subunits of the TARP, CKAMP and CNIH families are involved in Hebbian and homeostatic plasticity, which can be explained by their influence on surface trafficking and synaptic targeting. In conclusion, the series of studies covered in this review show that auxiliary subunits play a pivotal role in controlling information processing in the brain by modulating synaptic computation. [ABSTRACT FROM AUTHOR]

Background and Purpose: 17β estradiol (E2) rapidly regulates excitatory synaptic transmission at the classical Schaffer collateral (SC) input to hippocampal CA1 neurons. However, the impact of E2 on excitatory synaptic transmission at the distinct temporoammonic (TA) input to CA1 neurons and the oestrogen receptors involved is less clear.Experimental Approach: Extracellular recordings were used to monitor excitatory synaptic transmission in hippocampal slices from juvenile male (P11-24) Sprague Dawley rats. Immunocytochemistry combined with confocal microscopy was used to monitor the surface expression of the AMPA receptor (AMPAR) subunit, GluA1 in hippocampal neurons cultured from neonatal (P0-3) rats.Key Results: Here, we show that E2 induces a novel form of LTP at TA-CA1 synapses, an effect mirrored by the ERα agonist, PPT, and blocked by an ERα antagonist. ERα-induced LTP is NMDA receptor (NMDAR)-dependent and involves a postsynaptic expression mechanism that requires PI 3-kinase signalling and synaptic insertion of GluA2-lacking AMPARs. ERα-induced LTP has overlapping expression mechanisms with classical Hebbian LTP, as HFS-induced LTP occluded PPT-induced LTP and vice versa. In addition, activity-dependent LTP was blocked by the ERα antagonist, suggesting that ERα activation is involved in NMDA-LTP at TA-CA1 synapses.Conclusion and Implications: ERα induces a novel form of LTP at juvenile male hippocampal TA-CA1 synapses. As TA-CA1 synapses are implicated in episodic memory processes and are an early target for neurodegeneration, these findings have important implications for the role of oestrogens in CNS health and neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Key points In the hippocampus, calcium-permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood., In the present study, we looked for calcium-permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses., Computer modelling predicted (and experiments verified) that fast calcium-permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity., The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium-permeable AMPA receptors., Abstract AMPA-type glutamate receptors (AMPARs) lacking an edited GluA2 subunit are calcium-permeable (CP) and contribute to synaptic plasticity in several hippocampal interneuron types, although their precise role in the neocortex is not well described. We explored the presence of CP-AMPARs at pyramidal cell (PC) inputs to Martinotti cells (MCs) and basket cells (BCs) in layer 5 of the developing mouse visual cortex (postnatal days 12-21). GluA2 immunolabelling was stronger in MCs than in BCs. A differential presence of CP-AMPARs at PC-BC and PC-MC synapses was confirmed electrophysiologically, based on measures of spermine-dependent rectification and CP-AMPAR blockade by 1-naphtyl acetyl spermine using recordings from synaptically connected cell pairs, NPEC-AMPA uncaging and miniature current recordings. In addition, CP-AMPAR expression in BCs was correlated with rapidly decaying synaptic currents. Computer modelling predicted that this reduces spike latencies and sharpens suprathreshold responses in BCs, which we verified experimentally using the dynamic clamp technique. Thus, the synapse-specific expression of CP-AMPARs may critically influence both plasticity and information processing in neocortical microcircuits. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2012) 122, 891-899. Abstract Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca2+ levels in the cytosol and the formation of a Ca2+-calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca2+ underpinning this modulation is achieved, both, by Ca2+ entering via Ca2+-permeable KARs and, by the mobilization of intraterminal Ca2+ stores. Finally, we find that, congruent with the Ca2+-calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca2+-calmodulin activity. [ABSTRACT FROM AUTHOR]

AMPA-type ionotropic glutamate receptors (iGluRs) represent the major excitatory neurotransmitter receptor in the developing and adult vertebrate CNS. They are crucial for the normal hardwiring of glutamatergic circuits but also fine tune synaptic strength by cycling into and out of synapses during periods of sustained patterned activity or altered homeostasis. AMPARs are grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 receptor subunit. GluA2-containing receptors are thought to be the most abundant AMPAR in the CNS, typified by their small unitary events, Ca2+ impermeability and insensitivity to polyamine block. In contrast, GluA2-lacking AMPARs exhibit large unitary conductance, marked divalent permeability and nano- to micromolar polyamine affinity. Here, I review evidence for the existence of a third class of AMPAR which, though similarly Ca2+ permeable, is characterized by its near-insensitivity to internal and external channel block by polyamines. This novel class of AMPAR is most notably found at multivesicular release synapses found in the avian auditory brainstem and mammalian retina. Curiously, these synapses lack NMDA-type iGluRs, which are conventionally associated with controlling AMPAR insertion. The lack of NMDARs suggests that a different set of rules may govern AMPAR cycling at these synapses. AMPARs with similar functional profiles are also found on some glial cells suggesting they may have a more widespread distribution in the mammalian CNS. I conclude by noting that modest changes to the ion-permeation pathway might be sufficient to retain divalent permeability whilst eliminating polyamine sensitivity. Consequently, this emerging AMPAR subclass need not be assembled from novel subunits, yet to be cloned, but could simply occur by varying the stoichiometry of existing proteins. [ABSTRACT FROM AUTHOR]

Hebbian long-term potentiation (LTP) develops at specific synapses onto hippocampal CA1 oriens/alveus interneurons (OA-INs), suggesting selective regulation of distinct input pathways. Afferent-specific properties at interneuron synapses have been characterized extensively in CA3 stratum lucidum cells, but given interneuron diversity these rules of transmission and plasticity may not hold in other interneuron types. Here, we used paired recordings and demonstrate that CA2/3 pyramidal cell (PC) feedforward and CA1 PC feedback synapses onto OA-INs show distinct AMPA receptor rectification and Ca2+ permeability, short-term plasticity and mGluR2/3-mediated inhibition. Only feedback synapses undergo Hebbian LTP. OA-IN firing during repeated synaptic stimulation displays onset-transient or late-persistent responses consistent with activation of feedforward and feedback inputs, respectively. Input-output functions are preserved after theta-burst stimulation, but late-persistent responses selectively show mGluR1-dependent long-term increases. Thus, cell type- and afferent-specific rules of transmission and plasticity underlie distinct OA-IN input-output functions, providing selective long-term regulation in feedback inhibitory networks. [ABSTRACT FROM AUTHOR]

The hormone leptin crosses the blood brain barrier and regulates numerous neuronal functions, including hippocampal synaptic plasticity. Here we show that application of leptin resulted in the reversal of long-term potentiation (LTP) at hippocampal CA1 synapses. The ability of leptin to depotentiate CA1 synapses was concentration-dependent and it displayed a distinct temporal profile. Leptin-induced depotentiation was not associated with any change in the paired pulse facilitation ratio or the coefficient of variance, indicating a post-synaptic locus of expression. Moreover, the synaptic activation of NMDA receptors was required for leptin-induced depotentiation as the effects of leptin were blocked by the competitive NMDA receptor antagonist, D-aminophosphovaleric acid (D-AP5). The signaling mechanisms underlying leptin-induced depotentiation involved activation of the calcium/calmodulin-dependent protein phosphatase, calcineurin, but were independent of c- jun NH2 terminal kinase. Furthermore, leptin-induced depotentiation was accompanied by a reduction in α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor rectification indicating that loss of glutamate receptor 2 (GluR2)-lacking AMPA receptors underlies this process. These data indicate that leptin reverses hippocampal LTP via a process involving calcineurin-dependent internalization of GluR2-lacking AMPA receptors which further highlights the key role for this hormone in regulating hippocampal synaptic plasticity and neuronal development. [ABSTRACT FROM AUTHOR]