Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

Key Points

  • Oscillatory activity in the gamma frequency range (30–90 Hz) is a hallmark of the function of the hippocampal network. These oscillations are thought to be important for information processing.

  • Gamma oscillations can be replicated in in vitro models, in which the underlying mechanisms can be analysed systematically.

  • In all in vitro models, gamma oscillations are dependent on GABAA (γ-aminobutyric acid type A)-receptor-mediated inhibition, suggesting that these oscillations are primarily generated by networks of inhibitory interneurons.

  • Fast-spiking, parvalbumin-expressing basket cells are key components of the hippocampal interneuron network. They are extensively interconnected and fire action potentials that are phase-locked to the oscillations.

  • Interneuron network models that are based on mutual inhibition, assuming slow, weak and hyperpolarizing synapses, generate synchronized gamma activity if exposed to a tonic excitatory drive. However, these models are highly sensitive to heterogeneity in the drive.

  • Experimental analysis has revealed that basket cell–basket cell synapses are functionally specialized. They mediate fast, strong and shunting inhibition.

  • Realistic interneuron network models generate synchronized gamma activity with increased robustness against heterogeneity in the tonic excitatory drive.

  • Experimental analysis further reveals that basket cells are rapidly excited through gap junctions and fast glutamatergic synapses.

  • Both gap junctions and fast glutamatergic synapses stabilize gamma activity in interneuron networks.

  • Specialized synaptic properties turn the interneuron network into a robust gamma frequency oscillator. Therefore, interneuron networks might provide a precise reference signal for temporal encoding of information in principal neurons.

Abstract

Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.

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Figure 1: Networks of GABA-containing interneurons generate gamma oscillations in vitro.
Figure 2: Basket cells fire action potentials that are phase-locked to gamma oscillations in vivo and in vitro.
Figure 3: Functional specialization of GABA-mediated synaptic transmission in cortical interneuron networks in vitro.
Figure 4: Synchronization properties of interneuron network models.
Figure 5: 'Realistic' interneuron network models with fast, strong and shunting inhibitory synapses as well as gap junctions are optimal gamma frequency oscillators.
Figure 6: Several synaptic mechanisms underlie synchronization in interneuron networks during gamma oscillations.

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Acknowledgements

We thank J. Bischofberger, G. Buzsáki and D. Hansel for critical reading of earlier versions of this Review. The authors' work was supported by grants from the Deutsche Forschungsgemein-schaft (M.B., I.V. and P.J.), the Volkswagen Stiftung (M.B. and I.V.), the Human Frontiers Science Program Organization (P.J.) and the Bundesministerium für Bildung und Forschung (M.B., I.V. and P.J.). We apologize for the fact that owing to space constraints not all relevant papers could be cited.

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Correspondence to Peter Jonas.

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FURTHER INFORMATION

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Glossary

Divergence

The number of postsynaptic target neurons innervated by a particular neuron. By contrast, convergence is the number of presynaptic neurons innervating a given neuron.

Spatial coherence

The correlation between signals at two different locations for all times (whereas temporal coherence is the correlation between signals at two different times for the same location). The term was originally defined in physics, but is also widely used in neuroscience.

Parvalbumin

A calcium-binding protein that contains EF-hand (helix–loop–helix) motifs. In the hippocampus, parvalbumin is selectively expressed in fast-spiking basket cells and axo-axonic cells. Although the function of parvalbumin is not fully understood, its expression represents a reliable marker for interneuron identification.

Network models

Computational models of neuronal networks, in which individual neurons (integrate-and-fire or conductance-based elements) are coupled by inhibitory synapses, excitatory synapses or gap junctions.

Gap junctions

Morphologically specialized electrical and biochemical connections between two cells, which are formed by transcellular channels. A gap junction channel is composed of two hemichannels (connexons), each of which consists of six subunits (connexins). Gap junctions are blocked by octanol and carbenoxolone; however, these blockers are not absolutely specific.

Acute hippocampal slices

200–400-μm-thick sections of the hippocampus, typically cut with a tissue slicer in the transverse plane. In comparison to the in vivo brain, the acute slice offers easy access in electrophysiological experiments, excellent visibility and the possibility of fast solution exchange.

Basket cells

A well-defined type of soma-inhibiting GABA-containing interneuron, so named becaused of its formation of perisomatic 'baskets' around target cell somata. A large subset of basket cells have a fast-spiking action potential phenotype and express the calcium-binding protein parvalbumin.

Integrate-and-fire models

Simple models of the electrical behaviour of a single neuron, which is characterized by passive integration in the subthreshold voltage range and generation of a stereotypic spike above threshold. Networks with integrate-and-fire neurons can be treated analytically.

Conductance-based models

Models of the electrical behaviour of a single neuron in which active and passive properties are represented by voltage-dependent and leak conductances. The voltage dependency of sodium and potassium conductances, in turn, is often described in terms of Hodgkin–Huxley equations. Networks with conductance-based neurons require numerical analysis.

Tonic excitatory drive

Constant current or conductance that depolarizes neurons in network models above threshold, mimicking activation by mGluR agonists and other stimuli during experiments. The tonic excitatory drive can be either homogeneous (neurons receive the same drive) or heterogeneous (neurons receive different drives, with heterogeneity being quantified by a coefficient of variation).

Unitary IPSPs and IPSCs

Synaptic events generated by the activity of a single presynaptic neuron. IPSPs are measured under current-clamp conditions and IPSCs are measured under voltage-clamp conditions.

Compound IPSPs and IPSCs

Synaptic events generated by a population of presynaptic neurons, for example, evoked by stimulation of multiple presynaptic axons or synchronized activity in an interneuron network. The compound conductance is the convolution of the unitary conductance and the distribution of spike times and delays. Therefore, compound conductances have a slower time course than unitary conductances.

Synaptic depression

If GABA synapses are stimulated repetitively, the amplitude of the IPSCs often decreases. This phenomenon is known as paired-pulse depression (for a pair of stimuli) or multiple-pulse depression (for a train of stimuli). The opposite of depression is facilitation.

Gramicidin perforated-patch recording

Non-invasive whole-cell recording, in which the antibiotic gramicidin is used to obtain electrical access to the intracellular compartment. Gramidicin pores are impermeable to chloride. Therefore, the reversal potential of GABAA-receptor-mediated synaptic currents can be measured without perturbation.

EPSP

Membrane depolarization of the postsynaptic neuron following excitatory input, usually measured under current clamp conditions.

EPSC

Electric current, representing ion flow across a membrane, measured under voltage-clamp conditions.

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Bartos, M., Vida, I. & Jonas, P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8, 45–56 (2007). https://doi.org/10.1038/nrn2044

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