scholarly journals Neuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Simote T. Foliaki ◽  
Benjamin Schwarz ◽  
Bradley R. Groveman ◽  
Ryan O. Walters ◽  
Natalia C. Ferreira ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Gaba Receptors ◽  
Neurological Diseases ◽  
Gamma Oscillations ◽  
Normal Function ◽  
Neuronal Firing ◽  
Network Communication ◽  
Genetic Mutations ◽  
Gabaergic Inhibition ◽  
Neuronal Communication

AbstractThe neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNPE200K, trisomy 21 (T21), and LRRK2G2019S, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson’s disease. We utilized no known disease/healthy COs (HC) as normal function controls. At 3–4 and 6–10 months post-differentiation, COs with mutations showed no evidence of disease-related pathology. Electrophysiology assessment showed that all COs exhibited mature neuronal firing at 6–10 months old. At this age, we observed significant changes in the electrophysiology of the COs with disease-associated mutations (dCOs) as compared with the HC, including reduced neuronal network communication, slowing neuronal oscillations, and increased coupling of delta and theta phases to the amplitudes of gamma oscillations. Such changes were linked with the detection of hypersynchronous events like spike-and-wave discharges. These dysfunctions were associated with altered production and release of neurotransmitters, compromised activity of excitatory ionotropic receptors including receptors of kainate, AMPA, and NMDA, and changed levels and function of excitatory glutamatergic synapses and inhibitory GABAergic synapses. Neuronal properties that modulate GABAergic inhibition including the activity of Na–K-Cl cotransport 1 (NKCC1) in Cl− homeostasis and the levels of synaptic and extra-synaptic localization of GABA receptors (GABARs) were altered in the T21 COs only. The neurosteroid allopregnanolone, a positive modulator of GABARs, was downregulated in all the dCOs. Treatment with this neurosteroid significantly improved the neuronal communication in the dCOs, possibly through improving the GABAergic inhibition. Overall, without the manifestation of any disease-related pathology, the genetic mutations PRNPE200K, T21, and LRRK2G2019S significantly altered the neuronal network communication in dCOs by disrupting the excitatory-to-inhibitory balance.

Lévy noise-induced inverse stochastic resonance on Newman–Watts networks of Hodgkin–Huxley neurons

2020 ◽  
Vol 34 (19) ◽  
pp. 2050185
Author(s):  
Dongxi Li ◽  
Shuling Song ◽  
Ni Zhang
Keyword(s):  
Firing Rate ◽  
Stochastic Resonance ◽  
Neuronal Network ◽  
Coupling Strength ◽  
Stability Index ◽  
Neuronal Firing ◽  
Lévy Noise ◽  
Neuron Network ◽  
Average Firing Rate ◽  
Levy Noise

This paper primarily investigates the inverse stochastic resonance (ISR) of neuron network driven by Lévy noise with electrical autapse and chemical autapse, respectively. Firstly, the discharge of Hodgkin–Huxley (HH) neuron network under different noise parameters, autapse parameters and network coupling strength is shown. Then, the variation of average firing rate with Lévy noise in the case of electrical autapse and chemical autapse is presented. We find that there exists a minimum value of the average firing rate curve caused by stability index and noise intensity of Lévy noise across the whole network, which is the phenomenon of ISR. With the increase of autaptic intensity and coupling strength, the ISR inhibitory effect of neuron discharge is weakened. In addition, with the increase of coupling strength, the neuron discharge of neural network is more intense and regular. As a consequence, our work suggests that autaptic intensity and coupling efficient of neuronal network can regulate the neuronal firing activities and suppress the effect of ISR, and Lévy noise can induce ISR phenomenon in Newman–Watts neuronal network.

scholarly journals Dynamic Transitions in Neuronal Network Firing Sustained by Abnormal Astrocyte Feedback

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yangyang Yu ◽  
Zhixuan Yuan ◽  
Yongchen Fan ◽  
Jiajia Li ◽  
Ying Wu
Keyword(s):  
Neuronal Network ◽  
Epileptic Seizures ◽  
Neuronal Firing ◽  
Intensity Increase ◽  
Abnormal State ◽  
Synchronous Firing ◽  
Connection Probability ◽  
Neuronal Network Model ◽  
Hippocampal Ca3

Astrocytes play a crucial role in neuronal firing activity. Their abnormal state may lead to the pathological transition of neuronal firing patterns and even induce seizures. However, there is still little evidence explaining how the astrocyte network modulates seizures caused by structural abnormalities, such as gliosis. To explore the role of gliosis of the astrocyte network in epileptic seizures, we first established a direct astrocyte feedback neuronal network model on the basis of the hippocampal CA3 neuron-astrocyte model to simulate the condition of gliosis when astrocyte processes swell and the feedback to neurons increases in an abnormal state. We analyzed the firing pattern transitions of the neuronal network when astrocyte feedback starts to change via increases in both astrocyte feedback intensity and the connection probability of astrocytes to neurons in the network. The results show that as the connection probability and astrocyte feedback intensity increase, neuronal firing transforms from a nonepileptic synchronous firing state to an asynchronous firing state, and when astrocyte feedback starts to become abnormal, seizure-like firing becomes more severe and synchronized; meanwhile, the synchronization area continues to expand and eventually transforms into long-term seizure-like synchronous firing. Therefore, our results prove that astrocyte feedback can regulate the firing of the neuronal network, and when the astrocyte network develops gliosis, there will be an increase in the induction rate of epileptic seizures.

scholarly journals Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology

2019 ◽  
Vol 12 (603) ◽  
pp. eaay0300 ◽  
Author(s):  
Lucie I. Pisella ◽  
Jean-Luc Gaiarsa ◽  
Diabé Diabira ◽  
Jinwei Zhang ◽  
Ilgam Khalilov ◽  
...  
Keyword(s):  
Risk Factor ◽  
Social Behavior ◽  
Neurological Diseases ◽  
Ultrasonic Vocalizations ◽  
Network Activity ◽  
Gabaergic Inhibition ◽  
Developmental Sequence ◽  
Normal Cells ◽  
Neurological Pathology

KCC2 is a vital neuronal K+/Cl− cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007. We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.

Regulation of Chemical Autapse on an FHN-ML Neuronal System

2019 ◽  
Vol 29 (14) ◽  
pp. 1950202 ◽  
Author(s):  
Lianghui Qu ◽  
Lin Du ◽  
Honghui Zhang ◽  
Zilu Cao ◽  
Zichen Deng
Keyword(s):  
Phase Noise ◽  
Neuronal Network ◽  
Neuronal Firing ◽  
Resonance Phenomenon ◽  
Neuronal System ◽  
Discharge Mode ◽  
Neuronal Systems ◽  
High Level ◽  
Stochastic Resonance Phenomenon ◽  
Oscillatory Current

To explore the feasibility of physiological manipulation of autaptic structures, the effects of autaptic connections on an FHN-ML neuronal system with phase noise stimulation are studied systematically. Firstly, according to the dynamic analysis of the FHN-ML neuron model, a saddle-node bifurcation can occur on an invariant circle. Under the action of external oscillatory current with phase noise, the neuronal firing activity is sensitive to phase noise with less intensity, and an appropriate noise intensity can induce a significant stochastic resonance phenomenon. Secondly, the chemical autaptic function can effectively regulate the neuronal discharge activity. An inhibitory autapse can not only induce the transition from depolarized resting to periodic spiking, but can also induce the FHN-ML neuron suppressed by strong phase noise to generate a pronounced intermittent high-level burst-like discharge mode when the autaptic conductance is greater than 0.1. Finally, for a two-dimensional regular FHN-ML neuronal network, a small amount of autaptic structures can induce some special waveforms to restore the propagation of nerve impulses interrupted by phase noise disturbance. This indicates the significant regulation of autapses on spatial patterns of the FHN-ML neuronal network. The study can provide some theoretical guidance for building autaptic structures in local areas to modulate the dynamic behaviors of biological neuronal systems.

scholarly journals Altered GABAA,slow Inhibition and Network Oscillations in Mice Lacking the GABAA Receptor β3 Subunit

2009 ◽  
Vol 102 (6) ◽  
pp. 3643-3655 ◽  
Author(s):  
Harald Hentschke ◽  
Claudia Benkwitz ◽  
Matthew I. Banks ◽  
Mark G. Perkins ◽  
Gregg E. Homanics ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Gamma Oscillations ◽  
Theta Oscillations ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Gabaergic Inhibition ◽  
Wild Type ◽  
Hippocampal Network

Phasic GABAergic inhibition in hippocampus and neocortex falls into two kinetically distinct categories, GABAA,fast and GABAA,slow. In hippocampal area CA1, GABAA,fast is generally believed to underlie gamma oscillations, whereas the contribution of GABAA,slow to hippocampal rhythms has been speculative. Hypothesizing that GABAA receptors containing the β3 subunit contribute to GABAA,slow inhibition and that slow inhibitory synapses control excitability as well as contribute to network rhythms, we investigated the consequences of this subunit's absence on synaptic inhibition and network function. In pyramidal neurons of GABAA receptor β3 subunit-deficient (β3−/−) mice, spontaneous GABAA,slow inhibitory postsynaptic currents (IPSCs) were much less frequent, and evoked GABAA,slow currents were much smaller than in wild-type mice. Fittingly, long-lasting recurrent inhibition of population spikes was less powerful in the mutant, indicating that receptors containing β3 subunits contribute substantially to GABAA,slow currents in pyramidal neurons. By contrast, slow inhibitory control of GABAA,fast-producing interneurons was unaffected in β3−/− mice. In vivo hippocampal network activity was markedly different in the two genotypes. In β3−/− mice, epileptiform activity was observed, and theta oscillations were weaker, slower, less regular and less well coordinated across laminae compared with wild-type mice, whereas gamma oscillations were weaker and faster. The amplitude modulation of gamma oscillations at theta frequency (“nesting”) was preserved but was less well coordinated with theta oscillations. With the caveat that seizure-induced changes in inhibitory circuits might have contributed to the changes observed in the mutant animals, our results point to a strong contribution of β3 subunits to slow GABAergic inhibition onto pyramidal neurons but not onto GABAA,fast -producing interneurons and support different roles for these slow inhibitory synapses in the generation and coordination of hippocampal network rhythms.

scholarly journals DeepMQ: A Deep Learning Approach Based Myelin Quantification in Microscopic Fluorescence Images

2018 ◽  
Author(s):  
Sibel Çimen ◽  
Abdulkerim Çapar ◽  
Dursun Ali Ekinci ◽  
Umut Engin Ayten ◽  
Bilal Ersen Kerman ◽  
...  
Keyword(s):  
Image Analysis ◽  
Feature Extraction ◽  
Deep Learning ◽  
Neurological Diseases ◽  
Binary Classification ◽  
Signal Transmission ◽  
Machine Learning Techniques ◽  
Neuronal Communication ◽  
Learning Classifier ◽  
Learning Techniques

AbstractOligodendrocytes wrap around the axons and form the myelin. Myelin facilitates rapid neural signal transmission. Any damage to myelin disrupts neuronal communication leading to neurological diseases such as multiple sclerosis (MS). There is no cure for MS. This is, in part, due to lack of an efficient method for myelin quantification during drug screening. In this study, an image analysis based myelin sheath detection method, DeepMQ, is developed. The method consists of a feature extraction step followed by a deep learning based binary classification module. The images, which were acquired on a confocal microscope contain three channels and multiple z-sections. Each channel represents either oligodendroyctes, neurons, or nuclei. During feature extraction, 26-neighbours of each voxel is mapped onto a 2D feature image. This image is, then, fed to the deep learning classifier, in order to detect myelin. Results indicate that 93.38% accuracy is achieved in a set of fluorescence microscope images of mouse stem cell-derived oligodendroyctes and neurons. To the best of authors’ knowledge, this is the first study utilizing image analysis along with machine learning techniques to quantify myelination.

scholarly journals Dynamic 3D On-Chip BBB Model Design, Development, and Applications in Neurological Diseases

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3183
Author(s):  
Xingchi Chen ◽  
Chang Liu ◽  
Laureana Muok ◽  
Changchun Zeng ◽  
Yan Li
Keyword(s):  
Targeted Delivery ◽  
Neurological Diseases ◽  
In Vitro Models ◽  
Normal Function ◽  
Human Stem Cells ◽  
Design Development ◽  
High Throughput Drug Screening ◽  
The Central Nervous System ◽  
On Chip

The blood–brain barrier (BBB) is a vital structure for maintaining homeostasis between the blood and the brain in the central nervous system (CNS). Biomolecule exchange, ion balance, nutrition delivery, and toxic molecule prevention rely on the normal function of the BBB. The dysfunction and the dysregulation of the BBB leads to the progression of neurological disorders and neurodegeneration. Therefore, in vitro BBB models can facilitate the investigation for proper therapies. As the demand increases, it is urgent to develop a more efficient and more physiologically relevant BBB model. In this review, the development of the microfluidics platform for the applications in neuroscience is summarized. This article focuses on the characterizations of in vitro BBB models derived from human stem cells and discusses the development of various types of in vitro models. The microfluidics-based system and BBB-on-chip models should provide a better platform for high-throughput drug-screening and targeted delivery.

scholarly journals Neuron-specific knockouts indicate the importance of network communication to Drosophila rhythmicity

2019 ◽  
Author(s):  
M Schlichting ◽  
MM Diaz ◽  
J Xin ◽  
M Rosbash
Keyword(s):  
Gene Expression ◽  
Circadian Rhythms ◽  
Intercellular Communication ◽  
Clock Gene ◽  
Feedback Loops ◽  
Neuronal Firing ◽  
Network Communication ◽  
Constant Darkness ◽  
Circadian Period ◽  
Clock Gene Expression

AbstractAnimal circadian rhythms persist in constant darkness and are driven by intracellular transcription-translation feedback loops. Although these cellular oscillators communicate, isolated mammalian cellular clocks continue to tick away in darkness without intercellular communication. To investigate these issues in Drosophila, we assayed behavior as well as molecular rhythms within individual brain clock neurons while blocking communication within the ca. 150 neuron clock network. We also generated CRISPR-mediated neuron-specific circadian clock knockouts. The results point to two key clock neuron groups: loss of the clock within both regions but neither one alone has a strong behavioral phenotype in darkness; communication between these regions also contributes to circadian period determination. Under these dark conditions, the clock within one region persists without network communication. The clock within the famous PDF-expressing s-LNv neurons however was strongly dependent on network communication, likely because clock gene expression within these vulnerable sLNvs depends on neuronal firing or light.

Vigabatrin Induces Tonic Inhibition Via GABA Transporter Reversal Without Increasing Vesicular GABA Release

2003 ◽  
Vol 89 (4) ◽  
pp. 2021-2034 ◽  
Author(s):  
Yuanming Wu ◽  
Wengang Wang ◽  
George B. Richerson
Keyword(s):  
Patch Clamp ◽  
Gaba Receptors ◽  
Hippocampal Neurons ◽  
Gaba Release ◽  
Tonic Inhibition ◽  
Gabaergic Inhibition ◽  
Gaba Transporter ◽  
Whole Cell ◽  
Ambient Gaba

Two forms of GABAergic inhibition coexist: fast synaptic neurotransmission and tonic activation of GABA receptors due to ambient GABA. The mechanisms regulating ambient GABA have not been well defined. Here we examined the role of the GABA transporter in the increase in ambient [GABA] induced by the anticonvulsant vigabatrin. Pretreatment of cultured rat hippocampal neurons with vigabatrin (100 μM) for 2–5 days led to a large increase in ambient [GABA] that was measured as the change in holding current induced by bicuculline during patch-clamp recordings. In contrast, there was a decrease in the frequency of spontaneous miniature inhibitory postsynaptic currents mIPSCs with no change in their amplitude distribution, and a decrease in the magnitude of IPSCs evoked by presynaptic stimulation during paired recordings. The increase in ambient [GABA] was not prevented by blockade of vesicular GABA release with tetanus toxin or removal of extracellular calcium. During perforated patch recordings, the increase in ambient [GABA] was prevented by blocking the GABA transporter, indicating that the GABA transporter was continuously operating in reverse and releasing GABA. In contrast, blocking the GABA transporter increased ambient [GABA] during whole cell patch-clamp recordings unless GABA and Na+ were added to the recording electrode solution, indicating that whole cell recordings can lead to erroneous conclusions about the role of the GABA transporter in control of ambient GABA. We conclude that the equilibrium for the GABA transporter is a major determinant of ambient [GABA] and tonic GABAergic inhibition. We propose that fast GABAergic neurotransmission and tonic inhibition can be independently modified and play complementary roles in control of neuronal excitability.

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