Dataset Information

Dynamic Communications Between GABA_A Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

ABSTRACT: Several factors regulate cortical development, such as changes in local connectivity and the influences of dynamical synapses. In this study, we simulated various factors affecting the regulation of neural network activity during cortical development. Previous studies have shown that during early cortical development, the reversal potential of GABA_A shifts from depolarizing to hyperpolarizing. Here we provide the first integrative computational model to simulate the combined effects of these factors in a unified framework (building on our prior work: Khalil et al., 2017a,b). In the current study, we extend our model to monitor firing activity in response to the excitatory action of GABA_A. Precisely, we created a Spiking Neural Network model that included certain biophysical parameters for lateral connectivity (distance between adjacent neurons) and nearby local connectivity (complex connections involving those between neuronal groups). We simulated different network scenarios (for immature and mature conditions) based on these biophysical parameters. Then, we implemented two forms of Short-term synaptic plasticity (depression and facilitation). Each form has two distinct kinds according to its synaptic time constant value. Finally, in both sets of networks, we compared firing rate activity responses before and after simulating dynamical synapses. Based on simulation results, we found that the modulation effect of dynamical synapses for evaluating and shaping the firing activity of the neural network is strongly dependent on the physiological state of GABA_A. Moreover, the STP mechanism acts differently in every network scenario, mirroring the crucial modulating roles of these critical parameters during cortical development. Clinical implications for pathological alterations of GABAergic signaling in neurological and psychiatric disorders are discussed.

SUBMITTER: Khalil R

PROVIDER: S-EPMC6304749 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dynamic Communications Between GABA<sub>A</sub> Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

Khalil Radwa R Karim Ahmed A AA Khedr Eman E Moftah Marie M Moustafa Ahmed A AA

Frontiers in cellular neuroscience 20181217

Several factors regulate cortical development, such as changes in local connectivity and the influences of dynamical synapses. In this study, we simulated various factors affecting the regulation of neural network activity during cortical development. Previous studies have shown that during early cortical development, the reversal potential of GABA<sub>A</sub> shifts from depolarizing to hyperpolarizing. Here we provide the first integrative computational model to simulate the combined effects o ...[more]

PMID: 30618625

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Project description:Key pointsWe confirm that GABAB receptors (GABAB -Rs) are involved in the termination of Up-states; their blockade consistently elongates Up-states. GABAB -Rs also modulate Down-states and the oscillatory cycle, thus having an impact on slow oscillation rhythm and its regularity. The most frequent effect of GABAB -R blockade is elongation of Down-states and subsequent decrease of oscillatory frequency, with an increased regularity. In a quarter of cases, GABAB -R blockade shortened Down-states and increased oscillatory frequency, changes that are independent of firing rates in Up-states. Our computer model provides mechanisms for the experimentally observed dynamics following blockade of GABAB -Rs, for Up/Down durations, oscillatory frequency and regularity. The time course of excitation, inhibition and adaptation can explain the observed dynamics of the network. This study brings novel insights into the role of GABAB -R-mediated slow inhibition on the slow oscillatory activity, which is considered the default activity pattern of the cortical network.AbstractSlow wave oscillations (SWOs) dominate cortical activity during deep sleep, anaesthesia and in some brain lesions. SWOs are composed of periods of activity (Up states) interspersed with periods of silence (Down states). The rhythmicity expressed during SWOs integrates neuronal and connectivity properties of the network and is often altered under pathological conditions. Adaptation mechanisms as well as synaptic inhibition mediated by GABAB receptors (GABAB -Rs) have been proposed as mechanisms governing the termination of Up states. The interplay between these two mechanisms is not well understood, and the role of GABAB -Rs controlling the whole cycle of the SWO has not been described. Here we contribute to its understanding by combining in vitro experiments on spontaneously active cortical slices and computational techniques. GABAB -R blockade modified the whole SWO cycle, not only elongating Up states, but also affecting the subsequent Down state duration. Furthermore, while adaptation tends to yield a rather regular behaviour, we demonstrate that GABAB -R activation desynchronizes the SWOs. Interestingly, variability changes could be accomplished in two different ways: by either shortening or lengthening the duration of Down states. Even when the most common observation following GABAB -Rs blocking is the lengthening of Down states, both changes are expressed experimentally and also in numerical simulations. Our simulations suggest that the sluggishness of GABAB -Rs to follow the excitatory fluctuations of the cortical network can explain these different network dynamics modulated by GABAB -Rs.

Project description:Quantitative estimations of spatiotemporal complexity of cortical activity patterns are used in the clinic as a measure of consciousness levels, but the cortical mechanisms involved are not fully understood. We used a version of the perturbational complexity index (PCI) adapted to multisite recordings from the ferret (either sex) cerebral cortex in vitro (sPCI) to investigate the role of GABAergic inhibition in cortical complexity. We studied two dynamical states: slow-wave activity (synchronous state) and desynchronized activity, that express low and high causal complexity respectively. Progressive blockade of GABAergic inhibition during both regimes revealed its impact on the emergent cortical activity and on sPCI. Gradual GABAA receptor blockade resulted in higher synchronization, being able to drive the network from a desynchronized to a synchronous state, with a progressive decrease of complexity (sPCI). Blocking GABAB receptors also resulted in a reduced sPCI, in particular when in a synchronous, slow wave state. Our findings demonstrate that physiological levels of inhibition contribute to the generation of dynamical richness and spatiotemporal complexity. However, if inhibition is diminished or enhanced, cortical complexity decreases. Using a computational model, we explored a larger parameter space in this relationship and demonstrate a link between excitatory/inhibitory balance and the complexity expressed by the cortical network.SIGNIFICANCE STATEMENT The spatiotemporal complexity of the activity expressed by the cerebral cortex is a highly revealing feature of the underlying network's state. Complexity varies with physiological brain states: it is higher during awake than during sleep states. But it also informs about pathologic states: in disorders of consciousness, complexity is lower in an unresponsive wakefulness syndrome than in a minimally conscious state. What are the network parameters that modulate complexity? Here we investigate how inhibition, mediated by either GABAA or GABAA receptors, influences cortical complexity. And we do this departing from two extreme functional states: a highly synchronous, slow-wave state, and a desynchronized one that mimics wakefulness. We find that there is an optimal level of inhibition in which complexity is highest.

Dataset Information

Dynamic Communications Between GABA_A Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

Publications

Dynamic Communications Between GABA<sub>A</sub> Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

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Dataset Information

Dynamic Communications Between GABAA Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

Publications

Dynamic Communications Between GABA<sub>A</sub> Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dynamic Communications Between GABA_A Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.