The Mechanism of NMDA Receptor Mediated Increased in Gamma Oscillation Frequency

Activation of N-methyl-D-aspartate (NMDA) receptors has been shown to increase the frequency of gamma oscillations in the CA3 region of the hippocampus. The underlying mechanism of the increase however, is unclear. This project utilizes an integrate-and-fire model of the CA3, based on experimental data, to investigate the increase in oscillation frequency. The model was built first without NMDA receptors to simulate carbachol induced oscillations in vitro. Then, NMDA receptors were added to evoke the increase in oscillation frequency. The model shows that a shift in mechanism, from a pyramidal neuron-interneuron feedback loop, to interneuron-interneuron oscillations, is responsible for the increase in gamma oscillation frequency. An interesting relationship between the active NMDA mediated current and instantaneous cycle frequencies points to further areas of study

A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro

Basic cellular and network mechanisms underlying gamma frequency oscillations (30–80 Hz) have been well characterized in the hippocampus and associated structures. In these regions, gamma rhythms are seen as an emergent property of networks of principal cells and fast-spiking interneurons. In contrast, in the neocortex a number of elegant studies have shown that specific types of principal neuron exist that are capable of generating powerful gamma frequency outputs on the basis of their intrinsic conductances alone. These fast rhythmic bursting (FRB) neurons (sometimes referred to as "chattering" cells) are activated by sensory stimuli and generate multiple action potentials per gamma period. Here, we demonstrate that FRB neurons may function by providing a large-scale input to an axon plexus consisting of gap-junctionally connected axons from both FRB neurons and their anatomically similar counterparts regular spiking neurons. The resulting network gamma oscillation shares all of the properties of gamma oscillations generated in the hippocampus but with the additional critical dependence on multiple spiking in FRB cells

The Role of GLUK5-Containing Kainate Receptors in Entorhinal Cortex Gamma Frequency Oscillations

Using in vitro brain slices of hippocampus and cortex, neuronal oscillations in the frequency range of 30–80 Hz (gamma frequency oscillations) can be induced by a number of pharmacological manipulations. The most routinely used is the bath application of the broad-spectrum glutamate receptor agonist, kainic acid. In the hippocampus, work using transgenic kainate receptor knockout mice have revealed information about the specific subunit composition of the kainate receptor implicated in the generation and maintenance of the gamma frequency oscillation. However, there is a paucity of such detail regarding gamma frequency oscillation in the cortex. Using specific pharmacological agonists and antagonists for the kainate receptor, we have set out to examine the contribution of kainate receptor subtypes to gamma frequency oscillation in the entorhinal cortex. The findings presented demonstrate that in contrast to the hippocampus, kainate receptors containing the GLUK5 subunit are critically important for the generation and maintenance of gamma frequency oscillation in the entorhinal cortex. Future work will concentrate on determining the exact nature of the cellular expression of kainate receptors in the entorhinal cortex

The Role of GLUK5-Containing Kainate Receptors in Entorhinal Cortex Gamma Frequency Oscillations

Using in vitro brain slices of hippocampus and cortex, neuronal oscillations in the frequency range of 30–80 Hz (gamma frequency oscillations) can be induced by a number of pharmacological manipulations. The most routinely used is the bath application of the broad-spectrum glutamate receptor agonist, kainic acid. In the hippocampus, work using transgenic kainate receptor knockout mice have revealed information about the specific subunit composition of the kainate receptor implicated in the generation and maintenance of the gamma frequency oscillation. However, there is a paucity of such detail regarding gamma frequency oscillation in the cortex. Using specific pharmacological agonists and antagonists for the kainate receptor, we have set out to examine the contribution of kainate receptor subtypes to gamma frequency oscillation in the entorhinal cortex. The findings presented demonstrate that in contrast to the hippocampus, kainate receptors containing the GLUK5 subunit are critically important for the generation and maintenance of gamma frequency oscillation in the entorhinal cortex. Future work will concentrate on determining the exact nature of the cellular expression of kainate receptors in the entorhinal cortex

Acetylcholine modulates gamma frequency oscillations in the hippocampus by activation of muscarinic M1 receptors

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ejn.13582 This article is protected by copyright. All rights reserved.Modulation of gamma oscillations is important for the processing of information and the disruption of gamma oscillations is a prominent feature of schizophrenia and Alzheimer’s disease. Gamma oscillations are generated by the interaction of excitatory and inhibitory neurons where their precise frequency and amplitude are controlled by the balance of Accepted Article This article is protected by copyright. All rights reserved. excitation and inhibition. Acetylcholine enhances the intrinsic excitability of pyramidal neurons and supresses both excitatory and inhibitory synaptic transmission but the net modulatory effect on gamma oscillations is not known. Here, we find that the power, but not frequency, of optogenetically -induced gamma oscillations in the CA3 region of mouse hippocampal slices is enhanced by low concentrations of the broad spectrum cholinergic agonist carbachol but reduced at higher concentrations. This bidirectional modulation of gamma oscillations is replicated within a mathematical model by neuronal depolarization, but not by reducing synaptic conductances, mimicking the effects of muscarinic M1 receptor activation. The predicted role for M1 receptors was supported experimentally; bidirectional modulation of gamma oscillations by acetylcholine was replicated by a selective M1 receptor agonist and prevented by genetic deletion of M1 receptors. These results reveal that acetylcholine release in CA3 of the hippocampus modulates gamma oscillation power but not frequency in a bidirectional and dose -dependent manner by acting primarily through muscarinic M1 receptorsThis work was supported by the Wellcome Trust Neural Dynamics PhD programme (RTB) and the Wellcome Trust (JRM). We thank Eli Lilly and Co. for gifts of GSK -5 and M1 receptor knockout mice. We thank members of the Mellor lab for helpful discussions and J. Brown for comments on previous versions of the manuscript. The authors declare no competing financial interests

A különböző gátlósejttípusok hozzájárulása a hippokampális éleshullámok kialakulásához. = Contribution by distinct types of GABAergic interneuron to hippocampal sharp wave/ripple oscillations.

A hippokampusz neuronhálózatában spontán keletkeznek az éleshullámok, amelyek kulcsszerepet játszanak a memóriafolyamatokban. Egy in vitro modellt használva feltérképeztük az egyes idegsejttípusok bemeneti és kimeneti tulajdonságait az éleshullámok alatt. Az találtuk, hogy a legaktívabb gátlósejtek parvalbumint tartalmaztak, míg a piramissejtek többsége nem tüzelt. Meghatároztuk, hogy az éleshullámok alatti tüzelési aktivitás korrelált a serkentő szinaptikus bemenettel. Farmakológiai kísérletekkel kiderítettük, hogy a parvalbumin tartalmú gátlósejtek nagyfrekvenciás kisüléséből eredő periszomatikus gátló áramok generálják a lokális mezőpotenciálban mérhető éleshullámokat. Hasonlóan, ezek a gátlósejtek felelősek a gamma oszcillációk létrehozásáért is a hippokampális agyszeletekben. Ezen túlmenően megállapítottuk, hogy a kolinerg receptorok aktivációja, amely növeli a serkenthetőséget, de csökkenti a szinaptikus kommunikáció hatékonyságát, képes a hippokampusz alapműködését, az éleshullám-aktivitást átkapcsolni gamma oszcillációvá. Az eredményeink azt mutatják, hogy az éber állatra jellemző hálózati aktivitásokat, az éleshullámokat és a gamma oszcillációt ugyan az a hippokampális neuronhálózat generálja, amely a piramissejtek és a parvalbumin tartamú gátlósejtekből áll. | Sharp wave/ripple oscillations (SPW-Rs), that play a crucial role in memory formation, are spontaneously emerging synchronous network events in the hippocampal circuitry. Using an in vitro model, we uncovered that the input-output properties of distinct types of neurons during SPW-Rs. We found that the most active GABAergic cells were parvalbumin containing interneurons, while the vast majority of pyramidal cells was silent. Our analysis revealed that in all cell types the firing during SPW-Rs was driven by excitatory synaptic input. Pharmacological manipulations uncovered that perisomatic inhibitory currents predominantly originated from the high frequency discharge of parvalbumin containing interneurons generate the majority of the field potential that is seen as a sharp wave. Similarly, these GABAergic cells were found to generate the gamma oscillations in hippocampal slices as well. In addition, we elucidated that by cholinergic receptor activation, which increases the excitability, but reduces the efficiency of synaptic communication, the default mode of the hippocampal operation, the SPW-R state can be readily switched to gamma oscillation. Our results propose that the behaviorally relevant network activities, SPW-Rs and gamma oscillations are generated by the same neuronal circuitries in the hippocampus, comprised of pyramidal cells and parvalbumin containing interneurons

Modulation of hippocampal gamma oscillations by dopamine in heterozygous Reeler mice In vitro

The reelin haploinsufficient heterozygous reeler mouse (HRM), an animal model of schizophrenia, has altered mesolimbic dopaminergic pathways, shares similar neurochemical, and behavioral properties with the patients with schizophrenia. Dysfunctional neural circuitry with impaired gamma (γ) oscillation (30–80 Hz) has been implicated in abnormal cognition in patients with schizophrenia. However, the function of neural circuitry in terms of γ oscillation and its modulation by dopamine has not been reported in HRM. In this study, first, we recorded γ oscillations in CA3 from wide type (WT) mice and HRM hippocampal slices, and studied the effects of dopamine (DA) on γ oscillations. We found that there was no difference in γ power between WT mice and HRM and that dopamine increased γ power of WT mice but not HRM, suggesting that dopamine modulations of network oscillations in HRM are impaired. Second, we found that N-methyl-D-aspartate receptor (NMDAR) antagonist itself increased γ power and occluded DA-mediated enhancement of γ power in WT mice but partially restored DA modulation of γ oscillations in HRM. Third, inhibition of phosphoinositide 3-kinase (PI3K), a downstream molecule of NMDAR, increased γ power and blocked the effects of DA on γ oscillation in WT mice and had no significant effect on γ power but largely restored DA modulation of γ oscillations in HRM. Our results reveal that impaired DA function in HRM is associated with dysregulated NMDAR-PI3K signaling, a mechanism that may be relevant in the pathology of schizophrenia

Novel Candidate Genes Associated with Hippocampal Oscillations

The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD recombinant inbred mouse strains. Spontaneous activity and carbachol-induced fast network oscillations were analyzed with spectral and cross-correlation methods and the resulting traits were used for mapping quantitative trait loci (QTLs), i.e., regions on the genome that may influence hippocampal function. Using genome-wide hippocampal gene expression data, we narrowed the QTLs to eight candidate genes, including Plcb1, a phospholipase that is known to influence hippocampal oscillations. We also identified two genes coding for calcium channels, Cacna1b and Cacna1e, which mediate presynaptic transmitter release and have not been shown to regulate hippocampal network activity previously. Furthermore, we showed that the amplitude of the hippocampal oscillations is genetically correlated with hippocampal volume and several measures of novel environment exploration