Neuron-astrocyte Coupling Research Articles

Dynamic mechanisms of delay formation and propagation in neuronal astrocytic network with electromagnetic induction

A model of neuro-astrocytic coupling with electromagnetic induction has been developed to deeply investigate the genesis and propagation of Delay within networks. Delay is defined as the time neurons continue to fire after external stimulation has ceased until they reach a resting state. The findings reveal that the primary cause of Delay in the neuron-astrocyte coupling system is the role of astrocytes. We observe that within a certain range, the feedback intensity causes a fractal structure of Delay, and as the feedback from astrocytes intensifies, Delay increases indefinitely. Neurons can continue firing indefinitely post-stimulation, and we have identified the feedback threshold for this infinite Delay. Further, we observed the transmission of Delay in neuron-astrocyte networks. Subsequent neurons, which would not normally fire, begin to discharge during the transmission of Delay, a phenomenon induced by either synaptic or astrocytic coupling. Finally, with electromagnetic induction, we noted the cumulative effect of Delay in the network, leading to longer sustained firing in more distant neurons as the network extends and propagates. Our research elucidates the precise mechanisms of generation and propagation of Delay, offering insights akin to mechanisms of memory in the nervous system, potentially providing novel understandings in the field of cognitive science.

Effects of a Diabetic Microenvironment on Neurodegeneration: Special Focus on Neurological Cells.

Diabetes is a chronic metabolic condition associated with high levels of blood glucose which leads to serious damage to the heart, kidney, eyes, and nerves. Elevated blood glucose levels damage brain function and cognitive abilities. They also lead to various neurological and neuropsychiatric disorders, including chronic neurodegeneration and cognitive decline. High neuronal glucose levels can cause drastic neuronal damage due to glucose neurotoxicity. Astrocytes, a type of glial cell, play a vital role in maintaining brain glucose levels through neuron-astrocyte coupling. Hyperglycemia leads to progressive decline in neuronal networks and cognitive impairment, contributing to neuronal dysfunction and fostering a neurodegenerative environment. In this review, we summarize the various connections, functions, and impairments of glial cells due to metabolic dysfunction in the diabetic brain. We also summarize the effects of hyperglycemia on various neuronal functions in the diabetic brain.

The role of calcium dynamics with amyloid beta on neuron-astrocyte coupling

Amyloid beta ($A\beta$) plaques are associated with neurodegenerative diseases such as Alzheimer's disease. Due to the involvement of $A\beta$ plaques in the functioning of the brain; cognitive decline disrupts calcium homeostasis in nerve cells and causes abnormal calcium ions ($Ca^{2+}$) signaling patterns. In consequence, there is enhanced neuronal excitability, compromised synaptic transmission, and decreased astrocytic function. Neuron-astrocyte coupling through calcium dynamics with different neuronal functions has been studied. Key signaling molecules in this process include $Ca^{2+}$, which control several cellular functions, including neurotransmission and astrocytic regulation. The mathematical model for neuron-astrocyte communication has been developed to study the importance of calcium dynamics in signal transduction between the cells. To understand the wide role of mitochondria, NCX, and amyloid beta with various necessary parameters included in the model, $Ca^{2+}$ signaling patterns have been analyzed through amplitude modulation and frequency modulation. The results of the current model are simulated and analyzed using XPPAUT. The findings of the current study are contrasted with experimental data from an existing mathematical model that illustrates the impact of calcium oscillation frequency and amplitude modulations in nerve cells.

Memantine Improves the Disturbed Glutamine and γ-Amino Butyric Acid Homeostasis in the Brain of Rats Subjected to Experimental Autoimmune Encephalomyelitis.

Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate-glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron-astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA.

Resonance effects in neuronal-astrocyte model with ion channel blockage

Blockage of the specific ion channel is significant for neuronal dynamics. Astrocytes, the active partners of neurons, play the role of regulators of many neural activity processes. The effects of ion channel blockage and astrocyte responses to subthreshold periodic signals of different frequencies were investigated in a stochastic extended Hodgkin-Huxley model. We demonstrated that the neuronal response to weak signals is weakened by sodium channel blockage, whereas it is improved by modulating the degree of potassium channel blockage. There is a certain value of potassium channel blocking intensity, corresponding to the optimal response output, that is, the system has reached the resonance state. When taking the astrocyte into account, the system's response to weak stimuli can be enhanced a little. The more significant role of the astrocyte is that they have different responses to weak signals at different frequencies. The greater the neuron-astrocyte coupling strength factor, the better the response of the neuron to high-frequency weak signals. Therefore, we noted the phenomenon of “frequency selection” of the system's response to weak signals: at low frequencies, potassium channel blockage improves the response, whereas the astrocyte can modulate the neuronal response to external stimuli in the higher frequency range.

Vitamin C Recycling Regulates Neurite Growth in Neurospheres Differentiated In Vitro.

The reduced form of vitamin C, ascorbic acid (AA), has been related with gene expression and cell differentiation in the cerebral cortex. In neurons, AA is mainly oxidized to dehydroascorbic acid (DHA); however, DHA cannot accumulate intracellularly because it induces metabolic changes and cell death. In this context, it has been proposed that vitamin C recycling via neuron–astrocyte coupling maintains AA levels and prevents DHA parenchymal accumulation. To date, the role of this mechanism during the outgrowth of neurites is unknown. To stimulate neuronal differentiation, adhered neurospheres treated with AA and retinoic acid (RA) were used. Neuritic growth was analyzed by confocal microscopy, and the effect of vitamin C recycling (bystander effect) in vitro was studied using different cells. AA stimulates neuritic growth more efficiently than RA. However, AA is oxidized to DHA in long incubation periods, generating a loss in the formation of neurites. Surprisingly, neurite growth is maintained over time following co-incubation of neurospheres with cells that efficiently capture DHA. In this sense, astrocytes have high capacity to recycle DHA and stimulate the maintenance of neurites. We demonstrated that vitamin C recycling in vitro regulates the morphology of immature neurons during the differentiation and maturation processes.

Dynamical response of a neuron–astrocyte coupling system under electromagnetic induction and external stimulation**Project supported by the National Natural Science Foundation of China (Grant No. 11772242) and China Postdoctoral Science Foundation (Grant No. 2018M631140).

Previous studies have observed that electromagnetic induction can seriously affect the electrophysiological activity of the nervous system. Considering the role of astrocytes in regulating neural firing, we studied a simple neuron–astrocyte coupled system under electromagnetic induction in response to different types of external stimulation. Both the duration and intensity of the external stimulus can induce different modes of electrical activity in this system, and thus the neuronal firing patterns can be subtly controlled. When the external stimulation ceases, the neuron will continue to fire for a long time and then reset to its resting state. In this study, “delay” is defined as the delayed time from the firing state to the resting state, and it is highly sensitive to changes in the duration or intensity of the external stimulus. Meanwhile, the self-similarity embodied in the aforementioned sensitivity can be quantified by fractal dimension. Moreover, a hysteresis loop of calcium activity in the astrocyte is observed in the specific interval of the external stimulus when the stimulus duration is extended to infinity, since astrocytic calcium or neuron electrical activity in the resting state or during periodic oscillation depends on the initial state. Finally, the regulating effect of electromagnetic induction in this system is considered. It is clarified that the occurrence of “delay” depends purely on the existence of electromagnetic induction. This model can reveal the dynamic characteristics of the neuron–astrocyte coupling system with magnetic induction under external stimulation. These results can provide some insights into the effects of electromagnetic induction and stimulation on neuronal activity.

Spatiotemporal model of tripartite synapse with perinodal astrocytic process.

Information transfer may not be limited only to synapses. Therefore, the processes and dynamics of biological neuron-astrocyte coupling and intercellular interaction within this domain are worth investigating. Existing models of tripartite synapse consider an astrocyte as a point process. Here, we extended the tripartite synapse model by considering the astrocytic processes (synaptic and perinodal) as compartments. The scattered extrinsic signals in the extracellular space and the presence of calcium stores in different astrocytic sites create local transient [Ca2+]. We investigated the Ca2+ dynamics and found that the increase in astrocytic intracellular [Ca2+] enhances the probability of neurotransmitter release. However, the period in which the extrasynaptic glutamate lingers in the extracellular space may cause excitotoxicity. We propose further biological investigation on intercellular communication, considering that unconventional sources (nonsynaptic) of glutamate may improve information processing in neuron-astrocyte networks.

Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity

Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial β-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.

12. SYNAPTIC DYSFUNCTION IN SCHIZOPHRENIA: EXPLORATION OF NOVEL HYPOTHESES AND PROMISING NEW LEADS

Overall : Accumulating evidence suggests that bioenergetic function is impaired in the brain in schizophrenia. In normal brain, glucose is metabolized to lactate and pyruvate, which are monocarboxylate intermediates that serve as the primary energy source for neurons. Working memory and other cognitive domains are dependent on the shuttling of lactate from astrocytes to neurons. Defects in this complex pathway may underlie cognitive dysfunction in schizophrenia. The focus of this symposium is to present evidence of such defects, and to identify substrates that may be targeted for the development of new treatment strategies. Dr. Laura Rowland (University of Maryland, Baltimore, Maryland, USA) will present evidence of bioenergetic dysfunction in living subjects with schizophrenia. Increased levels of lactate (P < 0.05) were present in the ACC in schizophrenia (n = 27) compared to controls (n = 29). Higher lactate levels were associated with lowers scores on the MATRICS Consensus Cognitive Battery. These data establish a direct link between cognition and bioenergetic function in vivo in schizophrenia. Dr. Robert McCullumsmith (University of Cincinnati, Cincinnati, Ohio, USA) will present evidence of alterations in the lactate shuttle and glycolytic enzymes in postmortem samples from schizophrenia (n = 20) and control subjects (n = 20). Cell-subtype specific changes (P < 0.05) in transcripts include increased levels of the lactate transporter MCT4, decreased levels of the glycolytic enzymes PFK1 and hexokinase, and decreased levels of the glucose transporters Glut1 and Glut3. These data suggest attenuated glycolysis in pyramidal neurons, with a shift towards pathways that boost protection from oxidative stress. The last two speakers will present data that address mechanisms related to these findings, using animal models with behavioral endophenotypes of schizophrenia. Dr. Eduard Bentea (Free University of Brussels (VUB), Brussels, Belgium) will present data from the xCT knockout mouse showing that disruption of system xc-, which supports oxidative stress buffering mechanisms, leads to synaptic dysfunction. Specifically, electron microscopy studies indicate depletion of both pre-and post-synaptic glutamate, while electrophysiological studies show diminished excitatory postsynaptic potentials. These findings directly connect oxidative balance and extracellular glutamate levels with development of “broken” synapses, highlighting a potential mechanism for perturbation of bioenergetic coupling between astrocytes and neurons. Dr. Amy Ramsey (University of Toronto, Toronto, Canada) will present evidence from an animal model of synaptic dysfunction, the GluN1 knockdown mouse. These mice show a bioenergetic defect similar to schizophrenia, with decreased expression of glycolytic enzymes and glucose transporters. These translational findings indicate that genetic risk for schizophrenia may lead to an intermediate bioenergetic phenotype, where diminished supply of lactate and other energetic molecules to neurons could contribute to cognitive dysfunction. Taken together, the work presented by these speakers will provide a fresh look at the bioenergetic defects in schizophrenia, establishing that 1) metabolic perturbations in the brain are prominent and not just an effect antipsychotic treatment, 2) altered neuron-astrocyte coupling leads to synaptic dysfunction, and 3) genetic risk for “broken” synapses disrupts metabolic function.

Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation.

Diabetes milieu is a complex metabolic disease that has been known to associate with high risk of various neurological disorders. Hyperglycemia in diabetes could dramatically increase neuronal glucose levels which leads to neuronal damage, a phenomenon referred to as glucose neurotoxicity. On the other hand, the impact of hyperglycemia on astrocytes has been less explored. Astrocytes play important roles in brain energy metabolism through neuron-astrocyte coupling. As the component of blood brain barrier, glucose might be primarily transported into astrocytes, hence, impose direct impact on astrocyte metabolism and function. In the present study, we determined the effect of high glucose on the energy metabolism and function of primary astrocytes. Hyperglycemia level glucose (25 mM) induced cell cycle arrest and inhibited proliferation and migration of primary astrocytes. Consistently, high glucose decreased cyclin D1 and D3 expression. High glucose enhanced glycolytic metabolism, increased ATP and glycogen content in primary astrocytes. In addition, high glucose activated AMP-activated protein kinase (AMPK) signaling pathway in astrocytes. In summary, our in vitro study indicated that hyperglycemia might impact astrocyte energy metabolism and function phenotype. Our study provides a potential mechanism which may underlie the diabetic cerebral neuropathy and warrant further in vivo study to determine the effect of hyperglycemia on astrocyte metabolism and function.

A Theoretical Study on the Role of Astrocytic Activity in Neuronal Hyperexcitability by a Novel Neuron-Glia Mass Model.

Recent experimental evidence on the clustering of glutamate and GABA transporters on astrocytic processes surrounding synaptic terminals pose the question of the functional relevance of the astrocytes in the regulation of neural activity. In this perspective, we introduce a new computational model that embeds recent findings on neuron–astrocyte coupling at the mesoscopic scale intra- and inter-layer local neural circuits. The model consists of a mass model for the neural compartment and an astrocyte compartment which controls dynamics of extracellular glutamate and GABA concentrations. By arguments based on bifurcation theory, we use the model to study the impact of deficiency of astrocytic glutamate and GABA uptakes on neural activity. While deficient astrocytic GABA uptake naturally results in increased neuronal inhibition, which in turn results in a decreased neuronal firing, deficient glutamate uptake by astrocytes may either decrease or increase neuronal firing either transiently or permanently. Given the relevance of neuronal hyperexcitability (or lack thereof) in the brain pathophysiology, we provide biophysical conditions for the onset identifying different physiologically relevant regimes of operation for astrocytic uptake transporters.

Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: application to cerebral hypoxia

BackgroundIt is a daunting task to identify all the metabolic pathways of brain energy metabolism and develop a dynamic simulation environment that will cover a time scale ranging from seconds to hours. To simplify this task and make it more practicable, we undertook stoichiometric modeling of brain energy metabolism with the major aim of including the main interacting pathways in and between astrocytes and neurons.ModelThe constructed model includes central metabolism (glycolysis, pentose phosphate pathway, TCA cycle), lipid metabolism, reactive oxygen species (ROS) detoxification, amino acid metabolism (synthesis and catabolism), the well-known glutamate-glutamine cycle, other coupling reactions between astrocytes and neurons, and neurotransmitter metabolism. This is, to our knowledge, the most comprehensive attempt at stoichiometric modeling of brain metabolism to date in terms of its coverage of a wide range of metabolic pathways. We then attempted to model the basal physiological behaviour and hypoxic behaviour of the brain cells where astrocytes and neurons are tightly coupled.ResultsThe reconstructed stoichiometric reaction model included 217 reactions (184 internal, 33 exchange) and 216 metabolites (183 internal, 33 external) distributed in and between astrocytes and neurons. Flux balance analysis (FBA) techniques were applied to the reconstructed model to elucidate the underlying cellular principles of neuron-astrocyte coupling. Simulation of resting conditions under the constraints of maximization of glutamate/glutamine/GABA cycle fluxes between the two cell types with subsequent minimization of Euclidean norm of fluxes resulted in a flux distribution in accordance with literature-based findings. As a further validation of our model, the effect of oxygen deprivation (hypoxia) on fluxes was simulated using an FBA-derivative approach, known as minimization of metabolic adjustment (MOMA). The results show the power of the constructed model to simulate disease behaviour on the flux level, and its potential to analyze cellular metabolic behaviour in silico.ConclusionThe predictive power of the constructed model for the key flux distributions, especially central carbon metabolism and glutamate-glutamine cycle fluxes, and its application to hypoxia is promising. The resultant acceptable predictions strengthen the power of such stoichiometric models in the analysis of mammalian cell metabolism.