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      Stimulus-induced Epileptic Spike-Wave Discharges in Thalamocortical Model with Disinhibition

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      Scientific Reports
      Nature Publishing Group

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          Abstract

          Epileptic absence seizure characterized by the typical 2–4 Hz spike-wave discharges (SWD) are known to arise due to the physiologically abnormal interactions within the thalamocortical network. By introducing a second inhibitory neuronal population in the cortical system, here we propose a modified thalamocortical field model to mathematically describe the occurrences and transitions of SWD under the mutual functions between cortex and thalamus, as well as the disinhibitory modulations of SWD mediated by the two different inhibitory interneuronal populations. We first show that stimulation can induce the recurrent seizures of SWD in the modified model. Also, we demonstrate the existence of various types of firing states including the SWD. Moreover, we can identify the bistable parametric regions where the SWD can be both induced and terminated by stimulation perturbations applied in the background resting state. Interestingly, in the absence of stimulation disinhibitory functions between the two different interneuronal populations can also both initiate and abate the SWD, which suggests that the mechanism of disinhibition is comparable to the effect of stimulation in initiating and terminating the epileptic SWD. Hopefully, the obtained results can provide theoretical evidences in exploring dynamical mechanism of epileptic seizures.

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          Most cited references56

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          Cortical interneurons that specialize in disinhibitory control

          In the mammalian cerebral cortex, the diversity of interneuronal subtypes underlies a division of labor subserving distinct modes of inhibitory control 1–7 . A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation 8,9 . Although several interneuron populations are known to target other interneurons to varying degrees 10–15 , little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively 3,6,16,17 . During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell-type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.
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            Cellular mechanisms of a synchronized oscillation in the thalamus.

            Spindle waves are a prototypical example of synchronized oscillations, a common feature of neuronal activity in thalamic and cortical systems in sleeping and waking animals. Spontaneous spindle waves recorded from slices of the ferret lateral geniculate nucleus were generated by rebound burst firing in relay cells. This rebound burst firing resulted from inhibitory postsynaptic potentials arriving from the perigeniculate nucleus, the cells of which were activated by burst firing in relay neurons. Reduction of gamma-aminobutyric acidA (GABAA) receptor-mediated inhibition markedly enhanced GABAB inhibitory postsynaptic potentials in relay cells and subsequently generated a slowed and rhythmic population activity resembling that which occurs during an absence seizure. Pharmacological block of GABAB receptors abolished this seizure-like activity but not normal spindle waves, suggesting that GABAB antagonists may be useful in the treatment of absence seizures.
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              The mediodorsal thalamus drives feedforward inhibition in the anterior cingulate cortex via parvalbumin interneurons.

              Although the medial prefrontal cortex (mPFC) is classically defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD), the nature of information transfer between MD and mPFC is poorly understood. In sensory thalamocortical pathways, thalamic recruitment of feedforward inhibition mediated by fast-spiking, putative parvalbumin-expressing (PV) interneurons is a key feature that enables cortical neurons to represent sensory stimuli with high temporal fidelity. Whether a similar circuit mechanism is in place for the projection from the MD (a higher-order thalamic nucleus that does not receive direct input from the periphery) to the mPFC is unknown. Here we show in mice that inputs from the MD drive disynaptic feedforward inhibition in the dorsal anterior cingulate cortex (dACC) subregion of the mPFC. In particular, we demonstrate that axons arising from MD neurons directly synapse onto and excite PV interneurons that in turn mediate feedforward inhibition of pyramidal neurons in layer 3 of the dACC. This feedforward inhibition in the dACC limits the time window during which pyramidal neurons integrate excitatory synaptic inputs and fire action potentials, but in a manner that allows for greater flexibility than in sensory cortex. These findings provide a foundation for understanding the role of MD-PFC circuit function in cognition.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                23 November 2016
                2016
                : 6
                : 37703
                Affiliations
                [1 ]School of Mathematics and Physics, University of Science and Technology Beijing , Beijing 100083, P. R. China
                [2 ]Department of Dynamics and Control, Beihang University , Beijing 100191, P. R. China
                Author notes
                Article
                srep37703
                10.1038/srep37703
                5120301
                27876879
                c312250a-7da2-46d8-b2da-0ef0d6235325
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 03 August 2016
                : 03 November 2016
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