Kainate-induced Gamma Oscillations Research Articles

Histone Deacetylase Inhibitor Improves the Dysfunction of Hippocampal Gamma Oscillations and Fast Spiking Interneurons in Alzheimer's Disease Model Mice.

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

The actin binding protein drebrin helps to protect against the development of seizure-like events in the entorhinal cortex

The actin binding protein drebrin plays a key role in dendritic spine formation and synaptic plasticity. Decreased drebrin protein levels have been observed in temporal lobe epilepsy, suggesting the involvement of drebrin in the disease. Here we investigated the effect of drebrin knockout on physiological and pathophysiological neuronal network activities in mice by inducing gamma oscillations, involved in higher cognitive functions, and by analyzing pathophysiological epileptiform activity. We found that loss of drebrin increased the emergence of spontaneous gamma oscillations suggesting an increase in neuronal excitability when drebrin is absent. Further analysis showed that although the kainate-induced hippocampal gamma oscillations were unchanged in drebrin deficient mice, seizure like events measured in the entorhinal cortex appeared earlier and more frequently. The results suggest that while drebrin is not essential for normal physiological network activity, it helps to protect against the formation of seizure like activities during pathological conditions. The data indicate that targeting drebrin function could potentially be a preventive or therapeutic strategy for epilepsy treatment.

Modified Recording Chamber for Sustained Kainate-Induced Gamma Oscillations in Submerged Rat Hippocampal Slices

Fast neuronal network oscillations in an in vitro model are a challenging task. Here, we report that sustained gamma (31–35 Hz) oscillations can be induced by kainate (50 nM) in submerged rat hippocampal slices using modified Hajos’s type recording chamber with a superfusion inlet positioned close to the CA3 pyramidal cell layer. The general features of these kainate-induced gamma oscillations were similar to those previously reported in the hippocampal slices using the interface-type chamber and superfused hippocampus in vivo. We suggest that close positioning of the superfusion inlet improves oxygen supply and temperature control of the oscillation-generating network and that this modification could be useful in studies of the gamma rhythmogenesis in the submerged slices.

Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus.

Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region-specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models.

Ontogeny of kainate-induced gamma oscillations in the rat CA3 hippocampus in vitro.

GABAergic inhibition, which is instrumental in the generation of hippocampal gamma oscillations, undergoes significant changes during development. However, the development of hippocampal gamma oscillations remains largely unknown. Here, we explored the developmental features of kainate-induced oscillations (KA-Os) in CA3 region of rat hippocampal slices. Up to postnatal day P5, the bath application of kainate failed to evoke any detectable oscillations. KA-Os emerged by the end of the first postnatal week; these were initially weak, slow (20–25 Hz, beta range) and were poorly synchronized with CA3 units and synaptic currents. Local field potential (LFP) power, synchronization of units and frequency of KA-Os increased during the second postnatal week to attain gamma (30–40 Hz) frequency by P15–21. Both beta and gamma KA-Os are characterized by alternating sinks and sources in the pyramidal cell layer, likely generated by summation of the action potential—associated currents and GABAergic synaptic currents, respectively. Blockade of GABA(A) receptors with gabazine completely suppressed KA-Os at all ages indicating that GABAergic mechanisms are instrumental in their generation. Bumetanide, a NKCC1 chloride co-transporter antagonist which renders GABAergic responses inhibitory in the immature hippocampal neurons, failed to induce KA-Os at P2–4 indicating that the absence of KA-Os in neonates is not due to depolarizing actions of GABA. The linear developmental profile, electrographic features and pharmacological properties indicate that CA3 hippocampal beta and gamma KA-Os are fundamentally similar in their generative mechanisms and their delayed onset and developmental changes likely reflect the development of perisomatic GABAergic inhibition.

Sk-channel Agonist in Relation to Network Gamma-oscillations In-vitro

It is reported recently that sK-channels have implications in learning and memory processes and may serve as a potential target of memory impairment. Till now there is no in vitro data available on effect of sK-channel with respect to network oscillation that regulates consciousness based learning and memory tasks. In the present study we have test the effect of CyPPa on kainate-induced gamma oscillations. For induction of gamma oscillations in acute hippocampal slices from adult rats bath application of kainic acid 100 nM is used. Once the gamma oscillations have been stabilized, CyPPa is added into kainte solution to test its effect at 20 and 100 μM concentration. CyPPa (100 μM, n=6) blocked gamma oscillations in 25 ± 3min, increased in peak power is observed within 15 ± 3min of CyPPa application. Whereas, CyPPa (20 μM, n=6) blocked gamma oscillations induced by kainate 100 nM in 38 ± 5min. Further we have analyzed the effect of CyPPa on total peak power and power of dominant frequencies in bands (p We may conclude the network activity is altered by sK-channel agosnit Cyppa and resulted in overall reduction of network oscillatory activity in hippocampus.

Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses

Both neuregulin 1 (NRG1) and its receptor ErbB4 are susceptibility genes for schizophrenia. Reduced synchronization of evoked oscillations in several cortical regions, especially in the prefrontal cortex, is associated with the core symptoms of schizophrenia. Recent studies have reported that NRG1 may affect the hippocampal oscillations. However, the role of NRG1/ErbB4 signaling in the synchronization of neurons in the prefrontal cortex is unclear. Here, we found that NRG1 enhanced the synchrony of pyramidal neurons via presynaptic interneurons. Meanwhile, NRG1 also increased the synchrony between pairs of fast-spiking interneurons and pairs of fast-spiking and non-fast-spiking interneurons in the prefrontal cortex, and this effect was mediated by ErbB4 receptors. Moreover, the NRG1-enhanced synchrony of interneurons was through their mutually-inhibitory synapses but not electrical coupling. Furthermore, kainate-induced gamma oscillations in vivo were enhanced by NRG1 and did not change in Dlx5/6-ErbB4−/− mice in which the ErbB4 receptors were specifically knocked out in interneurons of the frontal brain. Overall, our findings suggested that NRG1/ErbB4 signaling plays an important role in the synchronized oscillations of the whole network in the prefrontal cortex that are impaired in schizophrenia.

Enhancement of gamma activity after selective activation of dopamine D4 receptors in freely moving rats and in a neurodevelopmental model of schizophrenia

Dopamine D4 receptor (D4R) mechanisms have been implicated in several psychiatric diseases, including schizophrenia, attention-deficit hyperactivity disorder (ADHD), and autism, which are characterized by cognitive deficits. The cellular mechanisms are poorly understood but impaired neuronal synchronization within cortical networks in the gamma frequency band has been proposed to contribute to these deficits. A D4R polymorphism was recently linked to variations in gamma power in both normal and ADHD subjects, and D4R activation was shown to enhance kainate-induced gamma oscillations in brain slices in vitro. The goal of this study was to investigate the effect of D4R activation on gamma oscillations in freely moving rats during natural behavior. Field potentials were recorded in the frontal, prefrontal, parietal, and occipital cortex and hippocampus. Gamma power was assessed before and after subcutaneous injection of a D4R agonist, A-412997, in several doses between 0.3 and 10.0mg/kg. The experiments were also repeated in a neurodevelopmental model of schizophrenia, in which rats are prenatally treated with methylazoxymethanol (MAM). We found that the D4R agonist increased gamma power in all regions at short latency and lasted for ~2h, both in normal and MAM-treated rats. The effect was dose dependent indicated by the significant difference between the effects after 3 and 10mg/kg in pair-wise comparison, whereas 0.3 and 1.0mg/kg injections were ineffective. This study demonstrates the involvement of D4R in cortical gamma oscillations in vivo and identifies this receptor as potential target for pharmacological treatment of cognitive deficits.

Kainate Induced Gamma Oscillations and Spike-Gamma Relationship Analysis

Kainate Induced Gamma Oscillations and Spike-Gamma Relationship Analysis

Long-Lasting Increase of Corticosterone After Fear Memory Reactivation: Anxiolytic Effects and Network Activity Modulation in the Ventral Hippocampus

Pathological fear and anxiety can be studied, in rodents, with fear conditioning and exposure to reminder cues. These paradigms are thought to critically involve the ventral hippocampus, which also serves as key site of glucocorticoid action in the brain. Here, we demonstrate a long-lasting reduction of kainate-induced gamma oscillations in slice preparations of the ventral hippocampal area CA3, 30 days after a single fear conditioning training. Reduction of gamma power was sensitive to corticosterone application and associated with a decrease in glucocorticoid and mineralocorticoid receptor mRNA expression across strata of the ventral hippocampal CA3. A fear reactivation session 24 h after the initial conditioning normalized receptor expression levels and attenuated the corticosterone-mediated recovery of gamma oscillations. It moreover increased both baseline and stimulus-induced corticosterone plasma levels and evoked a generalization of fear memory to the background context. Reduced ventral hippocampal gamma oscillation in both fear reactivated and non-reactivated mice were associated with a decrease of anxiety-like behavior in an elevated plus maze. Taking advantage of the circadian fluctuation in corticosterone, we demonstrated the association of high endogenous basal corticosterone plasma concentrations during morning hours with reduced anxiety-like behavior in fear reactivated mice. The anxiolytic effect of the hormone was verified with local applications to the ventral hippocampus. Our data suggest that corticosterone acting on ventral hippocampal network activity has anxiolytic-like effects following fear exposure, highlighting its potential therapeutic value for anxiety disorders.

Dopamine D4 Receptor Activation Increases Hippocampal Gamma Oscillations by Enhancing Synchronization of Fast-Spiking Interneurons

BackgroundGamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R) in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well.Methodology/Principal FindingsTo address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast-spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power.Conclusions/SignificanceWe conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor-dependent mechanism. This suggests that converging deficits on fast-spiking interneurons may lead to decreased network function and thus aberrant gamma oscillations and cognitive decline in schizophrenia.

In vitro hippocampal gamma oscillation power as an index of in vivo CA3 gamma oscillation strength and spatial reference memory

Neuronal synchronisation at gamma frequencies (30–100Hz) has been implicated in cognition and memory. Gamma oscillations can be studied in various invitro models, but their in vivo validity and their relationship with reference memory remains to be proven. By using the natural variation of wild type C57bl/6J mice, we assessed the relationships between reference memory and gamma oscillations recorded in hippocampal area CA3 in vivo and in vitro.Local field potentials (LFPs) were recorded from area CA3 in behaviourally-characterised freely moving mice, after which hippocampal slices were prepared for recordings in vitro of spontaneous gamma oscillations and kainate-induced gamma oscillations in CA3.The gamma-band power of spontaneous oscillations in vitro correlated with that of CA3 LFP oscillations during inactive behavioural states. The gamma-band power of kainate-induced oscillations correlated with the activity-dependent increase in CA3 LFP gamma-band power in vivo. Kainate-induced gamma-band power correlated with Barnes circular platform performance and object location recognition, but not with object novelty recognition. Kainate-induced gamma-band power was larger in mice that recognised the aversive context, but did not correlate with passive avoidance delay.The correlations between behavioural and electrophysiological measures obtained from the same animals show that the gamma-generating capacity of the CA3 network in vitro is a useful index of in vivo gamma strength and supports an important role of CA3 gamma oscillations in spatial reference memory.

Histamine H3 receptor activation decreases kainate‐induced hippocampal gamma oscillations in vitro by action potential desynchronization in pyramidal neurons

The study of rhythmic electrical activity in slice preparations has generated important insights into neural network function. While the synaptic mechanisms involved in the generation of in vitro network oscillations have been studied widely, little is known about the modulatory influence exerted on rhythmic activity in neuronal networks by neuropeptides and biogenic amines. Gamma oscillations play an important role in cognitive processes and are altered or disrupted in disorders such as Alzheimer's disease (AD) and schizophrenia. Given the importance of gamma oscillations for learning, memory and cognition processes as well as the recent interest in histamine H(3) receptors in the development of pro-cognitive drugs to treat disorders such as AD and schizophrenia, it is relevant to study the impact of histaminergic mechanisms on network gamma oscillations. Here we show for the first time a modulation of gamma oscillation by histaminergic mechanisms. Selective activation of the H(3) receptor by R-alpha-methylhistamine significantly reduces the power of kainate-induced gamma oscillations, but not carbachol-induced gamma oscillations, in the rat hippocampal slice preparation without affecting oscillation frequency. This effect is neither caused by a decrease in excitatory or inhibitory postsynaptic currents, nor a decrease in cellular excitability. Instead, we find that the decrease in oscillation power following H(3) receptor activation results from a desynchronization of pyramidal neuron action potential firing with regard to the local field potential oscillation cycle. Our data provide a possible mechanism of action for histamine in regulating gamma oscillations in the hippocampal network.

Kv7/KCNQ Channels Control Action Potential Phasing of Pyramidal Neurons during Hippocampal Gamma OscillationsIn Vitro

While the synaptic mechanisms involved in the generation of in vitro network oscillations have been widely studied, little is known about the importance of voltage-gated currents during such activity. Here we study the role of the M-current (I(M)) in the modulation of network oscillations in the gamma-frequency range (20-80 Hz). Kv7/KCNQ subunits, the molecular correlates of I(M), are abundantly expressed in CA1 and CA3 pyramidal neurons, and I(M) is an important modulator of pyramidal neuron firing. Using hippocampal slices, we recorded field activity and pyramidal neuron action potential timing during kainate-induced gamma oscillations. Application of the specific I(M) blocker XE991 causes a significant reduction of gamma oscillation amplitude with no significant change in oscillation frequency. Concomitant CA3 pyramidal neuron recordings show a significant increase in action potential frequency during ongoing gamma oscillations after the application of XE991. This increase is associated with a significant loss of periodicity of pyramidal neuron action potentials relative to the phase of the gamma oscillations. Using dynamic clamp, we show that I(M) acts to improve the periodicity of action potential timing and to decrease action potential frequency. We further validate these results in a compartmental model of a pyramidal neuron. Our work suggests that I(M) modulates gamma oscillations by regulating the phasing of action potential firing in pyramidal neurons.

Effect of ageing on CA3 interneuron sAHP and gamma oscillations is activity-dependent

Normal ageing-associated spatial memory impairment has been linked to subtle changes in the hippocampal network. Here we test whether the age-dependent reduction in gamma oscillations can be explained by the changes in intrinsic properties of hippocampal interneurons. Kainate-induced gamma oscillations, but not spontaneous gamma oscillations, were reduced in slices from aged mice. CA3 interneurons were recorded in slices from young and aged mice using Fura-2-filled pipettes. Passive membrane properties, firing properties, medium- and slow-afterhyperpolarisation amplitudes, basal [Ca(2+)](i) and firing-induced [Ca(2+)](i) transients were not different with ageing. Kainate caused a larger depolarisation and increase in [Ca(2+)](i) signal in aged interneurons than in young ones. In contrast to young interneurons, kainate increased the medium- and slow-afterhyperpolarisation and underlying [Ca(2+)](i) transient in aged interneurons. Modulating the slow-afterhyperpolarisation by modulating L-type calcium channels with BAY K 8644 and nimodipine suppressed and potentiated, respectively, kainate-induced gamma oscillations in young slices. The age-dependent and stimulation-dependent increase in basal [Ca(2+)](i), firing-induced [Ca(2+)](i) transient and associated afterhyperpolarisation may reduce interneuron excitability and contribute to an age-dependent impairment of hippocampal gamma oscillations.

Comparison between spontaneous and kainate‐induced gamma oscillations in the mouse hippocampus in vitro

Neuronal synchronization at gamma frequency, implicated in cognition, can be evoked in hippocampal slices by pharmacological activation. We characterized spontaneous small-amplitude gamma oscillations (SgammaO) recorded in area CA3 of mouse hippocampal slices and compared it with kainate-induced gamma oscillations (KgammaO). SgammaO had a lower peak frequency, a more sinusoidal waveform and was spatially less coherent than KgammaO, irrespective of oscillation amplitude. CA3a had the smallest oscillation power, phase-led CA3c by approximately 4 ms and had the highest SgammaO frequency in isolated subslices. During SgammaO CA3c neurons fired at the rebound of inhibitory postsynaptic potentials (IPSPs) that were associated with a current source in stratum lucidum, whereas CA3a neurons often fired from spikelets, 3-4 ms earlier in the cycle, and had smaller IPSPs. Kainate induced faster/larger IPSPs that were associated with an earlier current source in stratum pyramidale. SgammaO and KgammaO power were dependent on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, gap junctions and gamma-aminobutyric acid (GABA)(A) receptors. SgammaO was suppressed by elevating extracellular KCl, blocking N-methyl-d-aspartate (NMDA) receptors or muscarinic receptors, or activating GluR5-containing kainate receptors. SgammaO was not affected by blocking metabotropic glutamate receptors or hyperpolarization-activated currents. The adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethoxyxanthine (8-CPT) and the CB1 cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) increased SgammaO power, indicating that endogenous adenosine and/or endocannabinoids suppress or prevent SgammaO in vitro. SgammaO emerges from a similar basic network as KgammaO, but differs in involvement of somatically projecting interneurons and pharmacological modulation profile. These observations advocate the use of SgammaO as a natural model for hippocampal gamma oscillations, particularly during less activated behavioural states.

GluK2-Mediated Excitability within the Superficial Layers of the Entorhinal Cortex

Recent analysis of genetically modified mice deficient in different kainate receptor (KAR) subunits have strongly pointed to a role of the GluK2 subunit, mediating the vulnerability of the brain towards seizures. Research concerning this issue has focused mainly on the hippocampus. However, several studies point to a potential role of other parts of the hippocampal formation, in particular the entorhinal cortex, in the development of epileptic seizures. There is extensive cell death after such seizures in layer III of the medial entorhinal cortex (LIII mEC), making this region of special interest for investigation into related pathological conditions. We therefore characterized KAR mediated currents in LIII mEC pyramidal neurons by several different approaches. Using patch-clamp technique, in combination with glutamate uncaging in horizontal brain slices, we show that LIII mEC neurons exhibit KAR currents. Use of genetically modified mice reveal that these currents are mediated by GluK2 containing KARs. The IV curve indicates the predominant presence of a Ca2+ impermeable and edited form of the KAR. Finally, we show that GluK2 containing kainate receptors are essential for kainate-induced gamma oscillations within the entorhinal cortex.

Monoamines block kainate‐ and carbachol‐induced γ‐oscillations but augment stimulus‐induced γ‐oscillations in rat hippocampus in vitro

Monoamines are implicated in a cognitive processes in a variety of brain regions, including the hippocampal formation, where storage and retrieval of information are facilitated by synchronous network activities. We have investigated the effects of norepinephrine, serotonin, and dopamine on carbachol-, kainate-, and stimulus-induced hippocampal gamma-oscillations employing combined extra- and intracellular recordings. Monoamines dose-dependently and reversibly suppressed kainate- and carbachol-induced gamma-oscillations while increasing the frequency. The effect of serotonin was mimicked by fenfluramine, which releases serotonin from presynaptic terminals. Forskolin also suppressed kainate- and carbachol-induced gamma-oscillations. This effect was mimicked by 8-Br-cAMP and isoproterenol, an agonist of noradrenergic beta-receptor suggesting that the monoamines-mediated suppression of these oscillations could involve intracellular cyclic adenosine 3',5'-cyclic monophosphate (AMP). By contrast, stimulus-induced gamma-oscillations were dose-dependently augmented in power and duration after monoamines application. Intracellular recordings from pyramidal cells revealed that monoamines prolonged the stimulus-induced depolarization and membrane potential oscillations. Stimulus-induced gamma-oscillations were also suppressed by isoproterenol, the D1 agonist SKF-38393 forskolin, and 8-Br-cAMP. This suggests that the augmentation of stimulus-induced gamma-oscillations by monoamines involves--at least in part-different classes of cells than in case of carbachol- and kainate-induced gamma-oscillations.

Neural-Activity-Dependent Release of S100B from Astrocytes Enhances Kainate-Induced Gamma OscillationsIn Vivo

S100B is the principal calcium-binding protein of astrocytes and known to be secreted to extracellular space. Although secreted S100B has been reported to promote neurite extension and cell survival via its receptor [receptor for advanced glycation end products (RAGE)], effects of extracellular S100B on neural activity have been mostly unexplored. Here, we demonstrate that secreted S100B enhances kainate-induced gamma oscillations. Local infusion of S100B in S100B(-/-) mice enhanced hippocampal kainate-induced gamma oscillations in vivo. In a complementary set of experiments, local application of anti-S100B antibody in wild-type mice attenuated the gamma oscillations. Both results indicate that the presence of extracellular S100B enhances the kainate-induced gamma oscillations. In acutely isolated hippocampal slices, kainate application increased S100B secretion in a neural-activity-dependent manner. Further pharmacological experiments revealed that S100B secretion was critically dependent on presynaptic release of neurotransmitter and activation of metabotropic glutamate receptor 3. Moreover, the kainate-induced gamma oscillations were attenuated by the genetic deletion or antibody blockade of RAGE in vivo. These results suggest RAGE activation by S100B enhances the gamma oscillations. Together, we propose a novel pathway of neuron-glia communications--astrocytic release of S100B modulates neural network activity through RAGE activation.

Modulation of gamma oscillations by endogenous adenosine through A 1 and A 2A receptors in the mouse hippocampus

Adenosine serves as a homeostatic factor, regulating hippocampal activity through A 1 receptor-mediated inhibition. Gamma frequency oscillations, associated with cognitive functions, emerge from increased network activity. Here we test the hypothesis that hippocampal gamma oscillations are modulated by ambient adenosine levels. In mouse hippocampal slices exogenous adenosine suppressed the power of both kainate-induced gamma oscillations and spontaneous gamma oscillations, observed in a subset of slices in normal aCSF. Kainate-induced gamma oscillation power was suppressed by the A 1 receptor agonist PIA and potentiated by the A 1 receptor antagonist 8-CPT to three times matched control values with an EC 50 of 1.1 μM. 8-CPT also potentiated spontaneous gamma oscillation power to five times control values. The A 2A receptor agonist CGS21680 potentiated kainate-induced gamma power to two times control values (EC 50 0.3 nM), but this effect was halved in the presence of 8-CPT. The A 2A receptor antagonist ZM241385 suppressed kainate-induced gamma power. The non-selective adenosine receptor antagonist caffeine induced gamma oscillations in slices in control aCSF and potentiated both kainate-induced gamma and spontaneous gamma oscillations to three times control values (EC 50 28 μM). Decreasing endogenous adenosine levels with adenosine deaminase increased gamma oscillations. Increasing endogenous adenosine levels with the adenosine kinase inhibitor 5-iodotubericidin suppressed gamma oscillations. Partial hypoxia-induced suppression of gamma oscillations could be prevented by 8-CPT. These observations indicate that gamma oscillation strength is powerfully modulated by ambient levels of adenosine through A 1 receptors, opposed by A 2A receptors. Increased gamma oscillation strength is likely to contribute to the beneficial cognitive effects of caffeine.