Desynchronization of Neocortical Networks by Asynchronous Release of GABA at Autaptic and Synaptic Contacts from Fast-Spiking Interneurons

Frédéric Manseau,David A. Prince,Silvia Marinelli,John R. Huguenard,Alberto Bacci,Beat Schwaller,Pablo Méndez,Nelson Spruston

doi:10.1371/journal.pbio.1000492

Frédéric Manseau, David A. Prince + Show 6 more

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https://doi.org/10.1371/journal.pbio.1000492

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Abstract

Author SummaryIn the cerebral cortex (neocortex) of the brain, fast-spiking (FS) inhibitory cells contact many principal pyramidal (P) neurons on their cell bodies, which allows the FS cells to control the generation of action potentials (neuronal output). FS-cell-mediated rhythmic and synchronous inhibition drives coherent network oscillations of large ensembles of P neurons, indicating that FS interneurons are needed for the precise timing of cortical circuits. Interestingly, FS cells are self-innervated by GABAergic autaptic contacts, whose synchronous activation regulates FS-cell precise firing. Here we report that high-frequency firing in FS interneurons results in a massive (>10-fold), delayed, and prolonged (for seconds) increase in inhibitory events, occurring at both autaptic (FS–FS) and synaptic (FS–P) sites. This increased inhibition is due to asynchronous release of GABA from presynaptic FS cells. Delayed and disorganized asynchronous inhibitory responses significantly affected the input–output properties of both FS and P neurons, suggesting that asynchronous release of GABA might promote network desynchronization. FS interneurons can fire at high frequency (>100 Hz) in vitro and in vivo, and are known for their reliable and precise signaling. Our results show an unprecedented action of these cells, by which their tight temporal control of cortical circuits can be broken when they are driven to fire above certain frequencies.

Highlights

In the cerebral cortex, the control of neuronal population discharge pattern and timing is of fundamental importance for information processing and cognitive operations [1,2]
FS cells are self-innervated by GABAergic autaptic contacts, whose synchronous activation regulates FS-cell precise firing
This increased inhibition is due to asynchronous release of GABA from presynaptic FS cells

Summary

Introduction

The control of neuronal population discharge pattern and timing is of fundamental importance for information processing and cognitive operations [1,2]. Several factors likely contribute to making these interneurons highly specialized for the control of P spike precision, including their short membrane time constants; intrinsic excitability [15]; the presence of Kv3 potassium channels, which efficiently accelerate the repolarization of action potentials (APs) [16]; sub-millisecond AMPA receptor conductances [15,17,18,19]; the rapid and reliable synchronous release of GABA at their terminals [20,21,22,23]; the almost ubiquitous expression of the Ca2+binding protein parvalbumin (PV) in these cells; and the characteristic firing of APs at high constant rate with no adaptation Another factor that distinguishes FS cells from other interneuron types is their hypothesized rigid (non-plastic) action as precision devices during cortical operations, leading to the view that they represent a dedicated system for regulating the timing of activity in neocortical circuits [24,25].

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