Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.

Decades after the discovery that ionic zinc is present at high levels in glutamatergic synaptic vesicles, where, when, and how much zinc is released during synaptic activity remains highly controversial. Here we provide a quantitative assessment of zinc dynamics in the synaptic cleft and clarify its role in the regulation of excitatory neurotransmission by combining synaptic recordings from mice deficient for zinc signaling with Monte Carlo simulations. Ambient extracellular zinc levels are too low for tonic occupation of the GluN2A-specific nanomolar zinc sites on NMDA receptors (NMDARs). However, following short trains of physiologically relevant synaptic stimuli, zinc transiently rises in the cleft and selectively inhibits postsynaptic GluN2A-NMDARs, causing changes in synaptic integration and plasticity. Our work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses. By specifically moderating GluN2A-NMDAR signaling, zinc acts as a widespread activity-dependent regulator of neuronal circuits.

Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.

Presynaptic ionotropic glutamate receptors are emerging as key players in the regulation of synaptic transmission. Here we identify GluR7, a kainate receptor (KAR) subunit with no known function in the brain, as an essential subunit of presynaptic autoreceptors that facilitate hippocampal mossy fiber synaptic transmission. GluR7 ؊/؊ mice display markedly reduced short-and long-term synaptic potentiation. Our data suggest that presynaptic KARs are GluR6/ GluR7 heteromers that coassemble and are localized within synapses. We show that recombinant GluR6/GluR7 KARs exhibit low sensitivity to glutamate, and we provide evidence that presynaptic KARs at mossy fiber synapses are likely activated by high concentrations of glutamate. Overall, from our data, we propose a model whereby presynaptic KARs are localized in the presynaptic active zone close to release sites, display low affinity for glutamate, are likely Ca 2؉ -permeable, are activated by single release events, and operate within a short time window to facilitate the subsequent release of glutamate.kainate receptors ͉ presynaptic glutamate receptors ͉ short-term plasticity ͉ synaptic plasticity

Adenosine is a neuromodulator in the CNS that mainly acts through pre- and postsynaptic A(1) receptors to inhibit the release of excitatory neurotransmitters and NMDA receptor function. This might result from a highly localized distribution of A(1) receptors in the active zone and postsynaptic density of CNS synapses that we now investigated in the rat hippocampus. The binding density of the selective A(1) receptor antagonist, [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX), was enriched in membranes from Percoll-purified nerve terminals (B(max)=1839+/-52 fM/mg protein) compared to total membranes from the hippocampus (B(max)=984+/-31 fM/mg protein), the same occurring with A(1) receptor immunoreactivity. [3H]DPCPX binding occurred mainly to the plasma membrane rather than to intracellular sites, since the binding of the membrane permeable A(1) receptor ligand [3H]DPCPX to intact hippocampal nerve terminals (B(max)=1901+/-192 fM/mg protein) was markedly reduced (B(max)=321+/-30 fM/mg protein) by the membrane impermeable adenosine receptor antagonist, 8-sulfophenyltheophilline (25 microM). Further subcellular fractionation of hippocampal nerve terminals revealed that A(1) receptor immunoreactivity was strategically located in the active zone of presynaptic nerve terminals, as expected to understand the efficiency of A(1) receptors to depress neurotransmitter release. A(1) Receptors were also present in nerve terminals outside the active zone in accordance with the existence of a presynaptic A(1) receptor reserve. Finally, A(1) receptor immunoreactivity was evident in the postsynaptic density together with NMDA receptor subunits 1, 2A and 2B and with N-and P/Q-type calcium channel immunoreactivity, emphasizing the importance of A(1) receptors in the control of dendritic integration.

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Glutamate and NPY have been implicated in hippocampal neuropathology in temporal lobe epilepsy. Thus, we investigated the involvement of NPY receptors in mediating neuroprotection against excitotoxic insults in organotypic cultures of rat hippocampal slices. Exposure of hippocampal slice cultures to 2 µM AMPA (α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate) induced neuronal degeneration, monitored by propidium iodide uptake, of granule cells and CA1 pyramidal cells. For AMPA, whereas only the activation of Y2 receptors was effective for CA1 pyramidal cells. When the slice cultures were exposed to 6 µM kainate, the CA3 pyramidal cells displayed significant degeneration, and in this case the activation of Y1, Y2, and Y5 receptors was neuroprotective. For the kainic acid-induced degeneration of CA1 pyramidal cells, it was again found that only the Y2 receptor activation was effective. Based on the present findings, it was concluded that Y1, Y2, and Y5 receptors effectively can modify glutamate receptor-mediated neurodegeneration in the hippocampus.Key words: NPY • AMPA • kainate • neuroprotection • neurodegeneration N europeptide Y (NPY) is a 36-amino-acid peptide abundantly distributed in the brain and associated with a number of physiological and pathological conditions (1). This peptide has been shown to modulate anxiety, pain, memory, eating behavior, and many other functions in the central, as well as in the peripheral, nervous systems (1, 2). Another significant role of NPY that has become evident during the past decade is regulation of seizure activity (3).At least five NPY receptor subtypes have been identified based on different pharmacological profiles: Y1, Y2, Y4, Y5, and y6 (4). A putative Y3 receptor has also been identified (5 In the hippocampus, Y1 and Y2 receptors are highly expressed (11). Receptors of the Y1 subtype are preferentially located in granule cells of the dentate molecular layer, whereas Y2 receptors are expressed at high concentrations in the mossy fiber and Schaffer collateral fields (12). Moreover, Y5 receptor binding sites can also be found in the strata oriens and radiatum of the CA3 and CA1 areas (13,14). Presently, there is evidence for the involvement of these three NPY receptors subtypes in epilepsy. The activation of Y2 receptors suppresses seizure activity in hippocampal slices in vitro (15) and in vivo models (3). In human temporal lobe epilepsy, significant alterations in Y1 and Y2 receptor binding were observed (16). NPY Y5 receptors also seem to be involved in the suppression of seizure activity (17,18). In different animal models of epilepsy, NPY is highly expressed by granule cells and mossy fibers of the hippocampus (19,20), whereas in normal conditions only GABAergic interneurons express this peptide. Furthermore, knockout mice lacking the NPY gene develop spontaneous seizures and are more susceptible to pentylenetetrazol and kainic acid-induced motor seizures, which are inhibited by intracerebral infusion of NPY (21). Thus, these evidences suggest that N...

Progress in understanding the roles of kainate receptors (KARs) in synaptic integration, synaptic networks, and higher brain function has been hampered by the lack of selective pharmacological tools. We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors. We further show that UBP310 is an antagonist of recombinant GluK2/GluK5 receptors, the major population of KARs in the brain. Postsynaptic KAR receptor blockade at MF synapses significantly reduces the sustained depolarization, which builds up during repetitive activity, and impacts on spike transmission mediated by heterosynaptic signals. In addition, KARs present in aberrant MF synapses in the epileptic hippocampus were also blocked by UBP310. Our results support a specific role for postsynaptic KARs in synaptic integration of CA3 pyramidal cells and describe a tool that will be instrumental in understanding the physiopathological role of KARs in the brain.