NMDA receptor-dependent switching between different gamma rhythm-generating microcircuits in entorhinal cortex
25 Nov 2008-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 105, Iss: 47, pp 18572-18577
TL;DR: The two different gamma frequencies matched the different intrinsic frequencies in hippocampal areas CA3 and CA1, suggesting that NMDA receptor activation may control the nature of temporal interactions between mEC and hippocampus, thus influencing the pathway for information transfer between the two regions.
Abstract: Local circuits in the medial entorhinal cortex (mEC) and hippocampus generate gamma frequency population rhythms independently. Temporal interaction between these areas at gamma frequencies is implicated in memory—a phenomenon linked to activity of NMDA-subtype glutamate receptors. While blockade of NMDA receptors does not affect frequency of gamma rhythms in hippocampus, it exposes a second, lower frequency (25–35 Hz) gamma rhythm in mEC. In experiment and model, NMDA receptor-dependent mEC gamma rhythms were mediated by basket interneurons, but NMDA receptor-independent gamma rhythms were mediated by a novel interneuron subtype—the goblet cell. This cell was distinct from basket cells in morphology, intrinsic membrane properties and synaptic inputs. The two different gamma frequencies matched the different intrinsic frequencies in hippocampal areas CA3 and CA1, suggesting that NMDA receptor activation may control the nature of temporal interactions between mEC and hippocampus, thus influencing the pathway for information transfer between the two regions.
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TL;DR: The reported differences in the inhibitory microcircuitry in layer II of the MEC may have a profound functional impact on the computational working principles at different locations of the entorhinal network and influence the input pathways to the hippocampus.
90 citations
Cites background from "NMDA receptor-dependent switching b..."
...However, a functional hypothesis for this circuitry was lacking, except that it was shown to be responsible for gamma oscillations (Middleton et al., 2008), with reduced oscillatory power when PV+ neurons were ablated in a disease model (Cun- ningham et al., 2006)....
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TL;DR: Recent studies that determine the effect of ketamine on simple neurophysiological measures and to what extent they recapitulate findings in patients with schizophrenia are reviewed.
Abstract: Subanesthetic doses of the psychomimetic, ketamine, have been used for many years to elicit behavioral effects reminiscent of schizophrenia in both healthy humans and in animal models of the disease. More recently, there has been a move toward the use of simple neurophysiological measures (event-related potentials, brain oscillations) to assay the functional integrity of neuronal circuits in schizophrenia as these measures can be assessed in patients, healthy controls, intact animals, and even in brain slices. Furthermore, alterations of these measures are correlated with basic information processing deficits that are now considered central to the disease. Thus, here we review recent studies that determine the effect of ketamine on these measures and discuss to what extent they recapitulate findings in patients with schizophrenia. In particular, we examine methodological differences between human and animal studies and compare in vivo and in vitro effects of ketamine. Ketamine acts on multiple cortical and subcortical sites, as well as on receptors other than the N-methyl-d-aspartate receptor. Acute ketamine models' changes correlated with psychotic states (e.g. increased baseline gamma-band oscillations), whereas chronic ketamine causes cortical circuit changes and neurophysiological deficits (e.g. impaired event-related gamma-band oscillations) correlated with cognitive impairments in schizophrenia.
87 citations
Cites background from "NMDA receptor-dependent switching b..."
...However, since then, several studies using different technology have shown that NMDAR antagonist administration strongly increases the power of GBO in the visual cortex, auditory cortex, and prefrontal (prelimbic) cortex [130,131,146,147]....
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TL;DR: The results support the pyramidal-interneuron gamma model of fast rhythmic oscillation in the cerebral cortex and suggest that spike synchrony and phase preference arises from the precise interaction of excitatory–inhibitory postsynaptic currents.
Abstract: During the generation of higher-frequency (e.g., gamma) oscillations, cortical neurons can exhibit pairwise tight ( SIGNIFICANCE STATEMENT We dissected the cellular and synaptic basis of spike synchrony occurring at gamma frequency (30–80 Hz). We used simultaneous targeted whole-cell recordings in an active slice preparation and analyzed the relationships between synaptic inputs and spike generation. We found that both pyramidal and fast-spiking neurons receive large, coherent inhibitory synaptic inputs at gamma frequency. In addition, we found that fast-spiking interneurons receive large, phasic excitatory synaptic inputs immediately before spike generation followed shortly by synaptic inhibition. These data support the principal-interneuron gamma generation model, and reveal how the synaptic connectivity between excitatory and inhibitory neurons supports the generation of gamma oscillations and spike synchrony.
87 citations
Cites background from "NMDA receptor-dependent switching b..."
...…stimulation; Cardin et al., 2009; Sohal et al., 2009) or the artificial activation of metabotropic or ionotropic receptors (Whittington et al., 1995; Cunningham et al., 2003; Hájos et al., 2004; Mann et al., 2005; Tukker et al., 2007; Middleton et al., 2008; Atallah and Scanziani, 2009)....
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..., 2009) or the artificial activation of metabotropic or ionotropic receptors (Whittington et al., 1995; Cunningham et al., 2003; Hájos et al., 2004; Mann et al., 2005; Tukker et al., 2007; Middleton et al., 2008; Atallah and Scanziani, 2009)....
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TL;DR: It is shown that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex, and Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation.
Abstract: Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.
86 citations
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...However, even for inhibitionbased gamma rhythms ( 90 Hz), in vitro studies show different local codependent mechanisms (Gloveli et al., 2005; Middleton et al., 2008) and anatomical separation of sources across different laminae (Oke et al., 2010)....
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...However, even for inhibitionbased gamma rhythms ( 90 Hz), in vitro studies show different local codependent mechanisms (Gloveli et al., 2005; Middleton et al., 2008) and anatomical separation of sources across different laminae (Oke et al....
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01 Jan 2017
TL;DR: This article showed that negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses.
Abstract: New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.
85 citations
Cites background from "NMDA receptor-dependent switching b..."
...A key mechanism underlying the rapid antidepressant actions of ketamine in rodents (e.g., Kittelberger et al., 2012; Middleton et al., 2008; Hunt et al., 2011) and in humans (Cornwell et al., 2012; Driesen et al., 2013), as well as its hydroxynorketamine metabolites [e.g., (2R,6R)-HNK; Zanos et…...
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...A key mechanism underlying the rapid antidepressant actions of ketamine in rodents (e.g., Kittelberger et al., 2012; Middleton et al., 2008; Hunt et al., 2011) and in humans (Cornwell et al....
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References
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TL;DR: The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.
Abstract: We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.
2,404 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...This mechanism can underlie gamma rhythms in a broad range of frequencies from around 20 Hz up to 70 Hz in the hippocampus (8) but cannot support higher frequencies such as those labeled as ‘‘high gamma’’ previously (9)....
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TL;DR: It is proposed that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo.
Abstract: Partially synchronous 40-Hz oscillations of cortical neurons have been implicated in cognitive function. Specifically, coherence of these oscillations between different parts of the cortex may provide conjunctive properties to solve the 'binding problem': associating features detected by the cortex into unified perceived objects. Here we report an emergent 40-Hz oscillation in networks of inhibitory neurons connected by synapses using GABAA (gamma-aminobutyric acid) receptors in slices of rat hippocampus and neocortex. These network inhibitory postsynaptic potential oscillations occur in response to the activation of metabotropic glutamate receptors. The oscillations can entrain pyramidal cell discharges. The oscillation frequency is determined both by the net excitation of interneurons and by the kinetics of the inhibitory postsynaptic potentials between them. We propose that interneuron network oscillations, in conjunction with intrinsic membrane resonances and long-loop (such as thalamocortical) interactions, contribute to 40-Hz rhythms in vivo.
1,625 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...The basic mechanism of generation of population gamma rhythms by local neuronal circuits reveals an absolute dependence on the influence of fast spiking inhibitory interneurons at the level of principal cell somata (5, 6),with the frequency dependent on the magnitude and kinetics of gamma aminobutyric acid (GABAA) receptor-mediated synaptic events (7)....
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TL;DR: It is suggested that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus and that Gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
Abstract: The cellular generation and spatial distribution of gamma frequency (40-100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long axis of the dentate hilus, but average coherence decreased rapidly in the CA3 and CA1 directions. Analysis of short epochs revealed large fluctuations in coherence values between the dentate and CA1 gamma waves. Current source density analysis revealed large sinks and sources in the dentate gyrus with spatial distribution similar to the dipoles evoked by stimulation of the perforant path. The frequency changes of gamma and theta waves positively correlated (40-100 Hz and 5-10 Hz, respectively). Putative interneurons in the dentate gyrus discharged at gamma frequency and were phase-locked to the ascending part of the gamma waves recorded from the hilus. Following bilateral lesion of the entorhinal cortex the power and frequency of hilar gamma activity significantly decreased or disappeared. Instead, a large amplitude but slower gamma pattern (25-50 Hz) emerged in the CA3-CA1 network. We suggest that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus. We also hypothesize that under physiological conditions the hilar gamma oscillation may be entrained by the entorhinal rhythm and that gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.
1,529 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...For example, removal of entorhinal cortex in vivo produces a slower gamma rhythm (39), whose origins appear to be in area CA3 (40)....
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TL;DR: This work examines the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes and identifies two gamma generators, one in the dentate gyrus and another in the CA3-CA1 regions.
985 citations
"NMDA receptor-dependent switching b..." refers background in this paper
...For example, removal of entorhinal cortex in vivo produces a slower gamma rhythm (39), whose origins appear to be in area CA3 (40)....
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TL;DR: In this paper, the authors used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding.
Abstract: Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.
899 citations