Sleep slow oscillation and inhibition.

Igor Timofeev

Perspectives

Affiliation: Department Psychiatry and Neuroscience, School of Medicine, Université Laval, Québec,
QC G1V 0A6, Canada

CERVO brain research centre, Université Laval, Québec, QC G1J2G3, Canada

Correspondence:
Timofeev I
igor.timofeev@fmed.ulaval.ca

This is an Accepted Article that has been peer-reviewed and approved for publication in The Journal
of Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an
'Accepted Article'; doi: 10.1113/JP280146.

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When we fall asleep, fast electrical brain activities are progressively replaced by slower rhythms. The
major sleep rhythm is the slow oscillation, the cortically generated brain rhythm with a frequency
around 1 Hz. This rhythm coordinates activities of multiple other cortical rhythms. The slow
oscillation was initially described and investigated by Steriade and his co-workers in the early 90s.
They describe the slow oscillation (<1 Hz) in anesthetized cats as an alternation of depolarizing and
hyperpolarizing states of cortical neurons. A follow-up study that used simultaneous LFP and
intracellular recordings in anesthetized cats demonstrated that cortical hyperpolarization and silence
correspond to depth-positive (surface-negative) and cortical depolarization corresponds to depth-
negative (surface-positive) waves of LFP (Contreras & Steriade, 1995). The depolarizing components
of the slow oscillation are essentially composed of excitatory and inhibitory synaptic events, and
dendritic Ca2+ spikes occurring in both excitatory and inhibitory cortical neurons from all cortical
layers therefore they are often called active or UP states. During cortical active states, inhibitory
activities dominate over excitation. By contrast, hyperpolarizing states are periods of disfacilitation,
the network state at which synaptic activities are largely absent. Therefore, they are called silent or
DOWN states.

The slow oscillation originates in neocortex. It exists not only during slow-wave sleep, but also in
isolated cortical slabs in vivo, in neocortical slices, and cortical cell cultures in vitro. The cortical slow
oscillation has multiple subcortical controllers that influence its overall frequency or duration of
active or silent states. Activation of neuromodulatory systems blocks the slow oscillation and after
such activation the neocortex goes to permanent active states, which is characteristic of waking or
REM sleep. Blockage of thalamic inputs to the cortex dramatically increases the duration of cortical
silent states (Lemieux et al., 2014). A recent study demonstrated that claustrum neurons provide a
very efficient global control of cortical slow waves activity (Narikiyo et al., 2020). Not only the
claustrum neurons increase their firing prior to the onset of silent state, but they effectively trigger
the firing of parvalbumin-expressing GABAergic neurons right prior to the onset of silent state. Taken
together with several previous findings of possible thalamic activation of cortical inhibitory
interneurons one can conclude that the subcortical control of the slow oscillation is primarily
mediated via an activation of inhibition that precedes the onset of silent states. A vast majority of
previous studies demonstrated that GABAA (Cl -) -dependent inhibition was critically involved.

In this issue, The Journal of Physiology publishes an article by (Perez-Zabalza et al., 2020) that
provides evidences for a strong involvement of GABAB inhibition in the control of the cortical slow
oscillation. The study is composed of two major experimental approaches: electrophysiology in vitro,
and computational modelling. The slices of ferret brain placed in an artificial cerebrospinal solution
displayed slow oscillation patterns. The authors provide clear and strong evidences that blockage of
GABAB receptors consistently prolongs duration of UP states suggesting that activation of GABAB
receptors help to terminate UP states in agreement with the findings by Mann et al (2009). Effects
on DOWN state duration were variable. In about 75% of cases (typical network), blockage of GABAB
receptors increased the duration of DOWN states, but in the remaining cases (atypical network), the
same procedure decreased the duration of DOWN states revealing that the same effect in UP states
is compatible with opposite changes in the subsequent DOWN states. The blockage of GABAB
receptors also resulted in an increase in the regularity of slow oscillation, suggesting that the
physiological activation of GABAB receptors introduces irregularity and richness in the temporal
patterns. Similar changes occurred in both superficial- and deep cortical layers.

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The possible mechanisms of the network effects of GABAB receptor blockage were investigated in a
computational model. In the model, progressively growing excitation led to the onset of UP states.
Fast inhibition was following excitation with millisecond precision. The adaptation current led to the
termination of UP states, generating a rather regular cycle. In these conditions, adding GABAB
current invariantly increased the total inhibitory drive and the network went to DOWN state faster,
because the balance was shifted toward inhibition and dominating inhibition terminated self-
sustained activity during UP states.

The difference between typical and atypical network was modelled by manipulations of NMDA
conductance and adaptation current. In a typical network, the NMDA current was stronger, but to
maintain the overall duration of UP state, it was compensated by a larger adaptation current.
Blockage of GABAB inhibition increased the overall adaptation current. Because the adaptation
current is less stochastic than synaptic activities, it also decreased the variability of DOWN state
duration. The overall stronger excitatory drive during UP state increased the duration of following
down states.

The conclusions of the study are clear and very straightforward. What remains to be done in future
is to demonstrate that GABAB inhibition indeed plays a significant role in the generation of the slow
oscillation during sleep. Indeed, in this study, the UP states lasted roughly up to 0.5 sec and DOWN
states lasted somewhere between 2 and 3 sec. However, there is a large range of variability of
UP/DOWN durations depending on the brain state: e.g. slow wave sleep, type of anesthesia or
anesthesia levels. During slow-wave sleep the silent states last somewhere between 0.1 and 0.2 sec,
which represents about 10% of the duration of slow oscillation cycle. In ketamine-xylazine
anesthesia conditions, the anesthesia that among other effects blocks NMDA currents, the duration
of silent states was increased up to 0.4 sec, but duration of active states was shortened (Chauvette
et al., 2011). Under urethane anesthesia, the DOWN states appear to be even longer. Thus, we could
consider the possibility that the role of GABA B is not the same in all conditions. For example, how
GABAB would work during sleep. when UP states are long, and DOWN states are short is not
explained by the model presented in (Perez-Zabalza et al., 2020). Further experimental and
computational work is needed to elucidate the extent of the role played by GABAB inhibition in the
generation and control of slow oscillation during sleep.

There are multiple other questions that remain open: (a) Is there any specific role of activation of
pre- vs. postsynaptic GABAB receptors in the termination of UP states? (b) What kind of spontaneous
activity of GABAergic interneurons during UP states is needed in order to activate GABAB receptors?

Cortical slow oscillation has been investigated for more than a quarter of century. Despite this major
progress, we are yet far from a detailed understanding on how this rhythm is generated and
controlled.

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References:

Chauvette S, Crochet S, Volgushev M & Timofeev I. (2011). Properties of slow oscillation during slow-
wave sleep and anesthesia in cats. J Neurosci 31, 14998-15008.

Contreras D & Steriade M. (1995). Cellular basis of EEG slow rhythms: a study of dynamic
corticothalamic relationships. J Neurosci 15, 604-622.

Lemieux M, Chen J-Y, Lonjers P, Bazhenov M & Timofeev I. (2014). The impact of cortical
deafferentation on the neocortical slow oscillation. J Neurosci 34, 5689-5703.

Mann, E. O., Kohl, M. M., & Paulsen, O. (2009). Distinct roles of GABAA and GABAB receptors in
balancing and terminating persistent cortical activity. Journal of Neuroscience, 29(23), 7513-
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Narikiyo K, Mizuguchi R, Ajima A, Shiozaki M, Hamanaka H, Johansen JP, Mori K & Yoshihara Y.
(2020). The claustrum coordinates cortical slow-wave activity. Nature Neuroscience.

Perez-Zabalza M, Reig R, Manrique J, Jercog D, Winograd M, Parga N & Sanchez Vives MV. (2020).
Modulation of cortical slow oscillatory rhythm by GABA B receptors: an in vitro experimental
and computational study. J Physiol in press.

Competing Interests: I declare absence of conflict of interests.

Funding: Over last years my laboratory was supported by Canadian Institutes of Health Research
grants, MOP-136969, MOP-136967, National Institutes of Health Research NS104368, and National
Sciences and Engineering Research Council of Canada grant 298475.

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