Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition.

Mohit Dubey,Maria Pascual-Garcia,Maarten Hp Kole,Steven A Kushner,Dennis D Wever,Mustafa S Hamada,Koke Helmes

doi:10.7554/elife.73827

Mohit Dubey, Maria Pascual-Garcia + Show 5 more

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https://doi.org/10.7554/elife.73827

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Abstract

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations, but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here, using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals and increases failures, and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

Highlights

GABAergic interneurons play fundamental roles in controlling rhythmic activity patterns and the computational features of cortical circuits
We investigated in vivo cortical rhythms by recording local field potential (LFP) in layer 5 (L5)
In this study we identified that the cellular microarchitecture of myelination of PV+ BCs is required for stimulus-induced fast gamma frequencies, limiting the power of slow cortical oscillations and interictal spikes during quiet wakefulness

Summary

Introduction

GABAergic interneurons play fundamental roles in controlling rhythmic activity patterns and the computational features of cortical circuits. For PV+ BCs, the average path length between the axon initial segment (AIS) and release sites involved in local circuit inhibition is typically less than ~200 μm (Micheva et al, 2021; Schmidt et al, 2017; Tamás et al, 1997) and theoretical and experimental studies indicate the acceleration by myelin may play only a limited role in tuning inhibition (Micheva et al, 2021, 2016) Another notable long-standing hypothesis is that myelination of PV+ axons may be critical for the security and synchronous invasion of presynaptic terminals (Somogyi et al, 1983). BCs and examining the functional role of myelin by longitudinally examining the frequency spectrum of cortical oscillations

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Discussion

Methods