Arthur Bikbaev

Relationship of Hippocampal Theta and Gamma Oscillations to Potentiation of Synaptic Transmission

In the hippocampus in vivo, both synaptic plasticity and network activity are closely interdependent. We have found that immediately after an attempt to induce long-term potentiation (LTP), changes in theta (5–10 Hz) and gamma (30–100 Hz) activity correlate tightly with the occurrence of LTP, suggesting that tetanisation-driven activation of sensory inputs synchronises the activity of granule cells and interneurons, and thus, facilitates the encoding of acquired stimuli. This results in increase of theta and gamma power, and elevates the probability that afferent stimuli both coincide with the peak of theta cycle and reach their post-synaptic target within the gamma time-window (of 10–30 ms). Both these mechanisms can effectively shift the direction, of tetanisation-induced changes in synaptic weight, towards potentiation and induction of LTP. Here, we discuss our findings in the context of possible mechanisms that link theta and gamma oscillations with LTP induction, as well as their role in information processing and formation of memories.

MGluR5 mediates the interaction between late-LTP, network activity, and learning

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5–10 Hz) and gamma (30–100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.

Synaptically released matrix metalloproteinase activity in control of structural plasticity and the cell surface distribution of GluA1-AMPA receptors.

Synapses are particularly prone to dynamic alterations and thus play a major role in neuronal plasticity. Dynamic excitatory synapses are located at the membranous neuronal protrusions called dendritic spines. The ability to change synaptic connections involves both alterations at the morphological level and changes in postsynaptic receptor composition. We report that endogenous matrix metalloproteinase (MMP) activity promotes the structural and functional plasticity of local synapses by its effect on glutamate receptor mobility and content. We used live imaging of cultured hippocampal neurons and quantitative morphological analysis to show that chemical long-term potentiation (cLTP) induces the permanent enlargement of a subset of small dendritic spines in an MMP-dependent manner. We also used a superresolution microscopy approach and found that spine expansion induced by cLTP was accompanied by MMP-dependent immobilization and synaptic accumulation as well as the clustering of GluA1-containing AMPA receptors. Altogether, our results reveal novel molecular and cellular mechanisms of synaptic plasticity.

Midfrequency cortico-thalamic oscillations and the sleep cycle: Genetic, time of day and age effects

WAG/Rij rats have various types of mid frequency cortico-thalamic oscillations, such as anterior and posterior sleep spindles and two types of spike-wave discharges (SWD). The generalized SWD (type I) preferentially occur at transitions from wake to sleep, type II can be found at the occipital cortex during quite wakefulness. In the present experiment sleep spindles, SWD and sleep cycle characteristics of 6-month-old WAG/Rij rats were studied and compared with those of younger WAG/Rij rats with much less SWD and age-matched control (ACI) rats. EEG recordings were made during the beginning (morning) and end (afternoon) of the light period in these four groups of rats. Quantitative characteristics of SWD, sleep spindles and the sleep cycle were determined. There were strain-related and age-dependent effects in the various cortico-thalamic oscillations, older WAG/Rij had more SWDs than younger WAG/Rij rats (both types I and II) and there were more type I SWDs at the end of the light period compared to the beginning. Large strain, age and time of day effects on the sleep cycle were found. The duration of non-REM sleep and the sleep cycle was shorter in WAG/Rij rats but only at the end of the light period and only in older WAG/Rij rats. It can be concluded that the various phasic events and the length of the sleep cycle are under genetic control, and that the sleep cycle length is also controlled by time of day, age and genetic factors. Non-REM sleep and the sleep cycle are disrupted by absence seizures but only in fragile periods when drowsiness and light slow wave sleep dominate.

Hippocampal Network Activity is Transiently Altered by Induction of Long-Term Potentiation in the Dentate Gyrus of Freely Behaving Rats

A role for oscillatory activity in hippocampal neuronal networks has been proposed in sensory encoding, cognitive functions and synaptic plasticity. In the hippocampus, theta (5–10 Hz) and gamma (30–100 Hz) oscillations may provide a mechanism for temporal encoding of information, and the basis for formation and retrieval of memory traces. Long-term potentiation (LTP) of synaptic transmission, a candidate cellular model of synaptic information storage, is typically induced by high-frequency tetanisation (HFT) of afferent pathways. Taking into account the role of oscillatory activity in the processing of information, dynamic changes may occur in hippocampal network activity in the period during HFT and/or soon after it. These changes in rhythmic activity may determine or, at least, contribute to successful potentiation and, in general, to formation of memory. We have found that short-term potentiation (STP) and LTP as well LTP-failure are characterised with different profiles of changes in theta and gamma frequencies. Potentiation of synaptic transmission was associated with a significant increase in the relative theta power and mean amplitude of theta cycles in the period encompassing 300 seconds after HFT. Where LTP or STP, but not failure of potentiation, occurred, this facilitation of theta was accompanied by transient increases in gamma power and in the mean amplitude of gamma oscillations within a single theta cycle. Our data support that specific, correlated changes in these parameters are associated with successful synaptic potentiation. These findings suggest that changes in theta-gamma activity associated with induction of LTP may enable synaptic information storage in the hippocampus.

Brain extracellular matrix retains connectivity in neuronal networks.

The formation and maintenance of connectivity are critically important for the processing and storage of information in neuronal networks. The brain extracellular matrix (ECM) appears during postnatal development and surrounds most neurons in the adult mammalian brain. Importantly, the removal of the ECM was shown to improve plasticity and post-traumatic recovery in the CNS, but little is known about the mechanisms. Here, we investigated the role of the ECM in the regulation of the network activity in dissociated hippocampal cultures grown on microelectrode arrays (MEAs). We found that enzymatic removal of the ECM in mature cultures led to transient enhancement of neuronal activity, but prevented disinhibition-induced hyperexcitability that was evident in age-matched control cultures with intact ECM. Furthermore, the ECM degradation followed by disinhibition strongly affected the network interaction so that it strongly resembled the juvenile pattern seen in naïve developing cultures. Taken together, our results demonstrate that the ECM plays an important role in retention of existing connectivity in mature neuronal networks that can be exerted through synaptic confinement of glutamate. On the other hand, removal of the ECM can play a permissive role in modification of connectivity and adaptive exploration of novel network architecture.

Metabotropic glutamate receptor, mGlu5, regulates hippocampal synaptic plasticity and is required for tetanisation-triggered changes in theta and gamma oscillations

&NA; Hippocampal synaptic plasticity and learning are regulated by metabotropic glutamate receptors (mGlu) and particularly by mGlu5. In the hippocampus, synaptic plasticity is tightly linked to neuronal network oscillations in theta (5–10 Hz) and gamma (˜30–100 Hz) frequency ranges, and specific changes in theta and gamma spectral power can predict for the success of patterned afferent stimulation in inducing robust long‐term potentiation (LTP). In this study, we hypothesized that activation of mGlu5 mediates tetanisation‐driven changes in network oscillations and thereby determines the longevity of LTP. To explore this, we applied high‐frequency stimulation (HFS) to the perforant path input to the dentate gyrus (DG), in the presence of the negative allosteric modulator, 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP), or the positive allosteric modulator (S)‐(4‐fluorophenyl)‐[3‐(3‐(3‐(4‐fluorophenyl)‐[1,2,4]oxadiazol‐5‐yl)‐piperidin‐1‐yl)]methanone (ADX47273). In freely behaving rats, administration of MPEP resulted in a significant impairment, whereas treatment with ADX47273 led to a significant enhancement, of LTP (>24 h) compared to vehicle‐treated controls. Allosteric potentiation of mGlu5 also resulted in a significantly greater increase of the spectral power of theta and gamma oscillations within the period of 300 s after HFS, as compared to MPEP‐treated animals or controls. Our findings show that the regulation of hippocampal LTP by mGlu5 is associated with modulation of network oscillatory activity in the period shortly after LTP induction. Taken together, these data demonstrate that changes in the spectral contents of local field activity that occur in response to patterned afferent stimulation require activation of mGlu5 and may be instrumental for the successful expression of persistent LTP. This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’. HighlightsEnhancement of network oscillations after afferent stimulation predicts the longevity of LTP.Theta, gamma and epsilon frequency ranges are particularly relevant.Allosteric inhibition of mGlu5 suppresses oscillations that herald successful LTP.Allosteric potentiation of mGlu5 enhances LTP and associated oscillations.mGlu5, regulates hippocampal synaptic plasticity and associated changes in neuronal oscillations.

Molekulare Dynamik der neuronalen Informationsübertragung

Zusammenfassung Die detaillierte Analyse von Synapsen als verbindende Elemente zwischen Nervenzellen ist von zentraler Bedeutung, um sowohl die kognitiven Leistungen des Gehirns als auch deren Einschränkungen zu verstehen. Modernste optische Verfahren erlauben es heute, einzelne Moleküle in lebenden Zellen zu detektieren. Insbesondere kann so die Dynamik der molekularen Komposition in kleinsten Kompartimenten wie etwa den prä- und postynaptischen Membranen erforscht werden. Die Beobachtung der Verteilung von Rezeptoren, Ionenkanälen und Adhäsionsmolekülen über die Zeit lässt erkennen, dass diese einer ständigen stochastischen Bewegung unterliegen. Dies ist überraschend, sind doch Synapsen gerade für solche Proteinmoleküle als Akkumulationsorte mit vielen molekularen Anknüpfungspunkten beschrieben. Durch gezielte Beeinflussung der lateralen Bewegung von Glutamatrezeptoren in Verbindung mit klassischer Elektrophysiologie konnte gezeigt werden, dass die molekulare Dynamik entscheidend für die Induktion synaptischer Plastizität ist und ihrerseits durch synaptische Aktivität beeinflusst werden kann. Sie sollte daher auch mit Blick auf übergeordnete Hirnfunktionen und neurologische Erkrankungen näher untersucht werden.