Membrane resonance enables stable and robust gamma oscillations.
ABSTRACT: Neuronal mechanisms underlying beta/gamma oscillations (20-80 Hz) are not completely understood. Here, we show that in vivo beta/gamma oscillations in the cat visual cortex sometimes exhibit remarkably stable frequency even when inputs fluctuate dramatically. Enhanced frequency stability is associated with stronger oscillations measured in individual units and larger power in the local field potential. Simulations of neuronal circuitry demonstrate that membrane properties of inhibitory interneurons strongly determine the characteristics of emergent oscillations. Exploration of networks containing either integrator or resonator inhibitory interneurons revealed that: (i) Resonance, as opposed to integration, promotes robust oscillations with large power and stable frequency via a mechanism called RING (Resonance INduced Gamma); resonance favors synchronization by reducing phase delays between interneurons and imposes bounds on oscillation cycle duration; (ii) Stability of frequency and robustness of the oscillation also depend on the relative timing of excitatory and inhibitory volleys within the oscillation cycle; (iii) RING can reproduce characteristics of both Pyramidal INterneuron Gamma (PING) and INterneuron Gamma (ING), transcending such classifications; (iv) In RING, robust gamma oscillations are promoted by slow but are impaired by fast inputs. Results suggest that interneuronal membrane resonance can be an important ingredient for generation of robust gamma oscillations having stable frequency.
Project description:Distinct subtypes of inhibitory interneuron are known to shape diverse rhythmic activities in the cortex, but how they interact to orchestrate specific band activity remains largely unknown. By recording optogenetically tagged interneurons of specific subtypes in the primary visual cortex of behaving mice, we show that spiking of somatostatin (SOM)- and parvalbumin (PV)-expressing interneurons preferentially correlates with cortical beta and gamma band oscillations, respectively. Suppression of SOM cell spiking reduces the spontaneous low-frequency band (<30-Hz) oscillations and selectively reduces visually induced enhancement of beta oscillation. In comparison, suppressing PV cell activity elevates the synchronization of spontaneous activity across a broad frequency range and further precludes visually induced changes in beta and gamma oscillations. Rhythmic activation of SOM and PV cells in the local circuit entrains resonant activity in the narrow 5- to 30-Hz band and the wide 20- to 80-Hz band, respectively. Together, these findings reveal differential and cooperative roles of SOM and PV inhibitory neurons in orchestrating specific cortical oscillations.
Project description:<h4>Background</h4>Abnormal accumulation of amyloid ?<sub>1-42</sub> oligomers (A?O<sub>1-42</sub>), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how A?O<sub>1-42</sub> affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on A?O<sub>1-42</sub>-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP.<h4>Results</h4>Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that A?O<sub>1-42</sub> causes synapse-specific dysfunction in PV and SST interneurons. A?O<sub>1-42</sub> selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, A?O<sub>1-42</sub> selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such A?O<sub>1-42</sub>-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction.<h4>Conclusions</h4>Our results reveal that A?O<sub>1-42</sub> causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.
Project description:<h4>Background</h4>Gamma 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.<h4>Methodology/principal findings</h4>To 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.<h4>Conclusions/significance</h4>We 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.
Project description:Accumulation of amyloid ? oligomers (A?O) in Alzheimer's disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether A?O causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in A?O-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in A?O-injected mice selectively restored A?O-induced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from A?O-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus-response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that A?O increased the initial GABA release probability to depress SST/PV interneuron's inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons' input to CA1 PC as the synaptic mechanisms underlying A?O-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.
Project description:Dysfunction of parvalbumin (PV)-expressing interneurons is thought to underlie the alterations of gamma-band oscillations observed in schizophrenia. Although the pathomechanisms of this disease remain unclear, oxidative stress induced by NMDA receptor (NMDAR) hypofunction and decreased glutathione (GSH) synthesizing capacity have been shown to lead to PV-loss and aberrant oscillatory activity. However, the individual contributions of NMDAR-inhibition and GSH-depletion to the developmental alterations observed in schizophrenia are largely unknown. We therefore investigated each condition in isolation using hippocampal slice cultures wherein interneuron maturation occurs entirely in vitro. Although both treatments caused oxidative stress, NMDAR-inhibition led to an immediate reduction in gamma oscillation frequency and a delayed loss of PV. In contrast, GSH-depletion immediately decreased PV expression and increased power, without affecting frequency. Hence, although disturbances of PV-expression and gamma oscillations coexist in schizophrenia, they can arise from separate pathological processes.
Project description:Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in gamma-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance.
Project description:Gamma oscillations (30-150?Hz) in neuronal networks are associated with the processing and recall of information. We measured local field potentials in the dentate gyrus of freely moving mice and found that gamma activity occurs in bursts, which are highly heterogeneous in their spatial extensions, ranging from focal to global coherent events. Synaptic communication among perisomatic-inhibitory interneurons (PIIs) is thought to play an important role in the generation of hippocampal gamma patterns. However, how neuronal circuits can generate synchronous oscillations at different spatial scales is unknown. We analyzed paired recordings in dentate gyrus slices and show that synaptic signaling at interneuron-interneuron synapses is distance dependent. Synaptic strength declines whereas the duration of inhibitory signals increases with axonal distance among interconnected PIIs. Using neuronal network modeling, we show that distance-dependent inhibition generates multiple highly synchronous focal gamma bursts allowing the network to process complex inputs in parallel in flexibly organized neuronal centers.Perisomatic-inhibitory interneurons (PIIs) contribute to the generation of gamma oscillations in the hippocampus. Here the authors demonstrate distance-dependent inhibition between PIIs in freely moving mice, and use computational analysis to show that distance-dependent inhibition supports the emergence of focal gamma bursts.
Project description:The cellular diversity of interneurons in the neocortex is thought to reflect subtype-specific roles of cortical inhibition. Here we ask whether perturbations to two subtypes--parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons--can be compensated for with respect to their contributions to cortical development. We use a genetic cell fate switch to delete both PV+ and SST+ interneurons selectively in cortical layers 2-4 without numerically changing the total interneuron population. This manipulation is compensated for at the level of synaptic currents and receptive fields (RFs) in the somatosensory cortex. By contrast, we identify a deficit in inhibitory synchronization in vitro and a large reduction in cortical gamma oscillations in vivo. This reveals that, while the roles of inhibition in establishing cortical inhibitory/excitatory balance and RFs can be subserved by multiple interneuron subtypes, gamma oscillations depend on cellular properties that cannot be compensated for--likely, the fast signalling properties of PV+ interneurons.
Project description:Gamma-frequency oscillations depend on phasic synaptic GABA(A) receptor (GABA(A)R)-mediated inhibition to synchronize spike timing. The spillover of synaptically released GABA can also activate extrasynaptic GABA(A)Rs, and such tonic inhibition may also contribute to modulating network dynamics. In many neuronal cell types, tonic inhibition is mediated by delta subunit-containing GABA(A)Rs. We found that the frequency of in vitro cholinergically induced gamma oscillations in the mouse hippocampal CA3 region was increased by the activation of NMDA receptors (NMDARs) on interneurons. The NMDAR-dependent increase of gamma oscillation frequency was counteracted by the tonic inhibition of the interneurons mediated by delta subunit-containing GABA(A)Rs. Recordings of synaptic currents during gamma activity revealed that NMDAR-mediated increases in oscillation frequency correlated with a progressive synchronization of phasic excitation and inhibition in the network. Thus, the balance between tonic excitation and tonic inhibition of interneurons may modulate gamma frequency by shaping interneuronal synchronization.
Project description:Impaired synaptic neurotransmission may underly circuit alterations contributing to behavioral autism spectrum disorder (ASD) phenotypes. A critical component of impairments reported in somatosensory and prefrontal cortex of ASD mouse models are parvalbumin (PV)-expressing fast-spiking interneurons. However, it remains unknown whether PV interneurons mediating hippocampal networks crucial to navigation and memory processing are similarly impaired. Using PV-labeled transgenic mice, a battery of behavioral assays, in vitro patch-clamp electrophysiology, and in vivo 32-channel silicon probe local field potential recordings, we address this question in a Cntnap2-null mutant mouse model representing a human ASD risk factor gene. Cntnap2<sup>-/-</sup> mice show a reduction in hippocampal PV interneuron density, reduced inhibitory input to CA1 pyramidal cells, deficits in spatial discrimination ability, and frequency-dependent circuit changes within the hippocampus, including alterations in gamma oscillations, sharp-wave ripples, and theta-gamma modulation. Our findings highlight hippocampal involvement in ASD and implicate interneurons as a potential therapeutical target.