Roque, A. C. | bioRxiv Science

bioRxiv2025

Context-Dependent Modulation of Astrocytic Ca2+ Signals by Mitochondria - A Computational Study

Mitochondria are one of the major regulators of intracellular Ca2+ in the cells, uptaking this ion through the mitochondrial Ca2+ uniporter (MCU) and releasing by the mitochondrial permeability transition pore (mPTP). Astrocytes respond to neurotransmitters and other stimuli by increasing the intracellular Ca2+ concentration, a process called 2+ signaling. However, it is not clear how mitochondria interact with the neurotransmitter-triggered Ca2+ responses in astrocytes. To explore this mechanisms, we expanded a previous compartmental model of astrocytes developed by our group including the mitochondrial MCU and mPTP mechanisms controlling the Ca2+ response. We simulate glutamatergic and dopaminergic inputs, modeled as Poisson processes, that promote the synthesis of IP3 through the PLC pathway. Here, we used a unipolar and a bifurcated-terminal morphology models and, with exception for the distal compartments, every other compartment have mitochondria. Simulations revealed that mitochondria modulate the Ca2+ response in a context-dependent manner. For weak glutamatergic input, they reduce the frequency of Ca2+ oscillations and the distance these signals propagate from the terminal regions. However, for strong glutamatergic input and in the presence of dopamine, mitochondria enhance the Ca2+ response by reducing the Ca2+-dependent IP3 degradation. Our findings provide computational evidence that mitochondria have a critical role in shaping the spatial organization of Ca2+ singling in astrocytes.

neuroscience↗

bioRxiv2024

Diverse Calcium Signaling in Astrocytes: Insights from a Computational Model

Astrocytes are complex cells that influence a variety of brain functions and behaviors. They are active cells that show a sharp increase in intracellular Ca2+ concentration in response to neurotransmitters (events called Ca2+ signals). The main source of intracellular Ca2+ is the stores in endoplasmic reticulum (ER), released by the activation of IP3 receptor channels on the ER membrane. As neurons, astrocytes from different brain regions show distinct Ca2+ signals. In addition, astrocytes can also show different patterns of Ca2+ responses. It is not yet clear how the diversity of astrocyte response emerge from the same mech-anisms. Here we present a two variable astrocyte compartmental model for the Ca2+ and IP3 dynamics. We show that Ca2+ signals with different characteristics can emerge from changing the parameters associated with the Ca2+ and IP3 dynamics and the transmembrane current. We also show that global Ca2+ signals are required for the model to trigger different patterns of Ca2+ responses. The model present here can be used to simulate astrocytes from different brain regions and with distinct types of response.

neuroscience↗

bioRxiv2022

Dopamine facilitates the response to glutamatergic inputs in a computational model of astrocytes

Astrocytes are active cells that respond to neurotransmitters with elevations in their intracellular calcium concentration (calcium signals). In a tripartite synapse involving two neurons coupled by a glutamatergic synapse and one astrocyte, glutamate released by the presynaptic neuron can generate calcium signals in the astrocyte, which in turn trigger the release of neuroactive molecules (gliotransmitters) by the astrocyte that bind to receptors in the pre- and postsynaptic neuron membranes and modulate synaptic transmission. Astrocytic calcium signals can also be evoked by dopamine released in distant sites. Little is known about how dopamine modulates glutamatergic-evoked astrocyte activity. To investigate this question, we constructed compartmental astrocyte models with three different morphologies: linear (soma plus a single branch); branched (soma plus two branches); and bifurcated (soma plus a single branch that bifurcates into two branchlets). Compartments were modeled by conductance-based equations for membrane voltage and transport of ions, glutamate and dopamine between extra- and intracellular spaces. Glutamatergic and dopaminergic stimuli were modeled as Poisson processes with variable frequencies, and astrocyte responses were measured by number and location of evoked calcium signals. For cells with linear morphology, whole-cell dopaminergic stimulation reduced the glutamatergic stimulation frequency of distal compartments needed to generate calcium signals. For both the branched and bifurcated morphologies, whole-cell dopaminergic stimulation together with glutamatergic stimulation of one of the processes reduced the glutamatergic stimulation frequency necessary to trigger a calcium signal in the other process. The same glutamatergic stimulation protocols without dopamine stimulation required higher glutamatergic input frequencies to evoke calcium signals. Our results suggest that dopamine facilitates the occurrence of glutamatergic-evoked calcium signals, and that dopamine-glutamate interaction can control the distribution of calcium signals along the astrocyte extension. Author summaryAstrocytes are brain cells that are not electrically excitable as neurons but display chemical excitability in the form of transient rises in the intracellular calcium concentration (calcium signals) evoked by neurotransmitters. A tripartite synapse consists of pre- and postsynaptic terminals ensheathed by astrocyte processes. Neurotransmitters released by the presynaptic neuron can generate calcium signals in the astrocyte, which in turn trigger the release of neuroactive molecules (gliotransmitters) by the astrocyte that bind to receptors in the pre- and postsynaptic membranes and modulate synaptic transmission. Two neurotransmitters that can evoke astrocytic calcium signals are glutamate, the major neurotransmitter of excitatory synapses, and dopamine, an important modulatory neurotransmitter that can diffuse to wider regions than the synaptic release site. Little is known about how dopamine modulates glutamatergic-evoked astrocyte activity, and here we investigate this question using computational modeling. We constructed compartmental astrocyte models with three different morphologies: linear, with a single branch emanating from soma; branched, with two branches emanating from soma; and bifurcated, with a branch emanating from soma that bifurcates into two branchlets. Compartments were modeled by conductance-based equations for membrane voltage and transport of ions (sodium, potassium and calcium), glutamate and dopamine between extra- and intracellular spaces. Glutamatergic and dopaminergic stimuli were modeled as Poisson processes with variable frequencies. Astrocyte models with the three morphologies were submitted to similar stimulation protocols to compare their responses, which were measured in terms of the frequency and location of evoked calcium signals. For cells with linear morphology, dopaminergic stimulation of the entire cell (to simulate the diffuse action of dopamine) reduced the glutamatergic stimulation frequency of distal compartments (which simulates glutamatergic input from presynaptic neuron) needed to generate calcium signals. For both the branched and bifurcated morphologies, dopaminergic stimulation of the whole cell together with glutamatergic stimulation of the distal portions of one of the processes reduced the glutamate stimulation frequency necessary to trigger a calcium signal in the distal portions of the other process. Repetitions of the glutamatergic stimulation protocols without whole cell dopaminergic stimulation showed that higher glutamatergic input frequencies were needed to evoke calcium signals. Our results suggest that dopamine facilitates the occurrence of calcium signals evoked by glutamatergic inputs, and that interaction between dopamine and glutamate can control the distribution of calcium signals along the astrocyte extension.

neuroscience↗

bioRxiv2020

A unified theory of E/I synaptic balance, quasicritical neuronal avalanches and asynchronous irregular spiking

Neuronal avalanches and asynchronous irregular (AI) firing patterns have been thought to represent distinct frameworks to understand the brain spontaneous activity. The former is typically present in systems where there is a balance between the slow accumulation of tension and its fast dissipation, whereas the latter is accompanied by the balance between synaptic excitation and inhibition (E/I). Here, we develop a new theory of E/I balance that relies on two homeostatic adaptation mechanisms: the short-term depression of inhibition and the spike-dependent threshold increase. First, we turn off the adaptation and show that the so-called static system has a typical critical point commonly attributed to self-organized critical models. Then, we turn on the adaptation and show that the network evolves to a dynamic regime in which: (I) E/I synapses balance regardless of any parameter choice; (II) an AI firing pattern emerges; and (III) neuronal avalanches display power laws. This is the first time that these three phenomena appear simultaneously in the same network activity. Thus, we show that the once thought opposing frameworks may be unified into a single dynamics, provided that adaptation mechanisms are in place. In our model, the AI firing pattern is a direct consequence of the hovering close to the critical line where external inputs are compensated by threshold growth, creating synaptic balance for any E/I weight ratio. HighlightsO_LIAsynchronous irregular (AI) firing happens together with power-law neuronal avalanches under self-organized synaptic balance. C_LIO_LISelf-organization towards the critical and balanced state (with AI and power-law avalanches) occur via short-term inhibition depression and firing threshold adaptation. C_LIO_LIThe avalanche exponents match experimental findings. C_LIO_LIThe adaptation time scales drive the self-organized dynamics towards different firing regimes. C_LI Author summaryTwo competing frameworks are employed to understand the brain spontaneous activity, both of which are backed by computational and experimental evidence: globally asynchronous and locally irregular (AI) activity arises in excitatory/inhibitory balanced networks subjected to external stimuli, whereas avalanche activity emerge in excitable systems on the critical point between active and inactive states. Here, we develop a new theory for E/I networks and show that there is a state where synaptic balance coexists with AI firing and power-law distributed neuronal avalanches. This regime is achieved through the introducing of short-term depression of inhibitory synapses and spike-dependent threshold adaptation. Thus, the system self-organizes towards the balance point, such that its AI activity arises from quasicritical fluctuations. The need for two independent adaptive mechanisms explains why different dynamical states are observed in the brain.

neuroscience↗

bioRxiv2019

Binding of Filamentous Actin to CaMKII as a Potential Mechanism for the Regulation of Bidirectional Synaptic Plasticity by betaCaMKII in Cerebellar Purkinje Cells

Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the {beta} isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how {beta}CaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that {beta}CaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the {beta} isoform of the kinase to regulate bidirectional plasticity at these synapses.\n\nAuthor SummaryMany molecules and the complex interactions between them are involved in synaptic plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) is an important component of the signalling network that is responsible for plasticity in cerebellar Purkinje cells (PCs). The CaMKII holoenzyme contains different isoforms such as CaMKII and {beta}CaMKII. Experiments with Camk2b knockout mice that lack the {beta} isoform of CaMKII demonstrated that {beta}CaMKII regulates the direction of plasticity at parallel fibre (PF)-PC synapses. Stimulation protocols that induce long-term depression in wild-type mice, which contain both and {beta}CaMKII, lead to long-term potentiation in knockout mice without {beta}CaMKII, and vice versa. We developed a kinetic simulation of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B to investigate how {beta}CaMKII can control bidirectional synaptic plasticity in cerebellar PCs. Our simulation results demonstrate that the binding of filamentous actin to {beta}CaMKII can contribute to the regulation of bidirectional plasticity at PF-PC synapses. Our computational model of intracellular signalling significantly advances the understanding of the mechanisms of synaptic plasticity induction in the cerebellum.

neuroscience↗

bioRxiv2019

Binding of Filamentous Actin to CaMKII as a Potential Mechanism for the Regulation of Bidirectional Plasticity by βCaMKII in Cerebellar Purkinje Cells

Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the {beta} isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how {beta}CaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that {beta}CaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the {beta} isoform of the kinase to regulate bidirectional plasticity at these synapses.\n\nAuthor SummaryMany molecules and the complex interactions between them are involved in synaptic plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) is an important component of the signalling network that is responsible for plasticity in cerebellar Purkinje cells (PCs). The CaMKII holoenzyme contains different isoforms such as CaMKII and {beta}CaMKII. Experiments with Camk2b knockout mice that lack the {beta} isoform of CaMKII demonstrated that {beta}CaMKII regulates the direction of plasticity at parallel fibre (PF)-PC synapses. Stimulation protocols that induce long-term depression in wild-type mice, which contain both and {beta}CaMKII, lead to long-term potentiation in knockout mice without {beta}CaMKII, and vice versa. We developed a kinetic simulation of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B to investigate how {beta}CaMKII can control bidirectional synaptic plasticity in cerebellar PCs. Our simulation results demonstrate that the binding of filamentous actin to {beta}CaMKII can contribute to the regulation of bidirectional plasticity at PF-PC synapses. Our computational model of intracellular signalling significantly advances the understanding of the mechanisms of synaptic plasticity induction in the cerebellum.

neuroscience↗

bioRxiv2018

Goalkeeper game: a new assessment instrument in neurology showed higher predictive power than moca for gait performance in people with parkinson’s disease

ObjectiveTo investigate the use of the Goalkeeper Game (GG) to assess gait automaticity decline under dual task conditions in people with Parkinsons disease (PPD) and compare its predictive power with the one of the MoCA test.\n\nMaterials and Methods74 PPD (H&Y stages: 23 in stage 1; 31 in stage 2; 20 in stage 3), without dementia (MoCA cut-off 23), tested in ON period with dopaminergic medication were submitted to single individual cognitive/motor evaluation sessions. The tests applied were: MoCA, GG, dynamic gait index (DGI) task and timed up and go test (TUG) under single and dual-task (DT) conditions. GG test resulted in 9 measures extracted via a statistical model. The predictive power of the GG measures and the MoCA score with respect to gait performance, as assessed by DGI and DT-TUG, were compared.\n\nResultsThe predictive models based on GG measures and MoCA score obtained, respectively, sensitivities of 65% and 56% for DGI scores and 59% and 57% for DT-TUG cost at a 50% specificity. GG application proved to be feasible and aroused more motivation in PPDs than MoCa.\n\nConclusionGG, a friendly and ludic game, was able to reach a good power of gait performance prediction in people at initial and intermediate stages of PD evolution.

neuroscience↗

bioRxiv2018

Reimplementation of the Potjans-Diesmann cortical microcircuit model: from NEST to Brian

1This work targets the replicability of computational models to provide the community with tested and proven open-source models to be used in new studies and implementations. The Potjans-Diesmann model describes a cortical microcircuit containing two cell types (excitatory and inhibitory) distributed in four layers, and represents the cortical network below a surface of 1 mm2. The original implementation of the Potjans-Diesmann model was based on the NEST simulator and our goal here was to re-implement the model in the Brian 2 simulator and obtain the same results presented in the reference article. We did not replicate analyses that involve changes in the network structure. Our replicated network model presents activity dynamic patterns very similar to the ones observed in the original model, with comparisons made in terms of firing rates and synchrony and irregularity measures. In conclusion, the Potjans-Diesmann model was successfully replicated in a different platform than the one in which it was originally implemented.

systems biology↗

bioRxiv2017

Effects of altered excitation-inhibition balance on decision making in a cortical circuit model

BackgroundDisruption of the synaptic balance between excitation and inhibition (E/I balance) in cortical circuits is a leading hypothesis for pathophysiologies of neuropsychiatric disorders, such as schizophrenia. However, it is poorly understood how synaptic E/I disruptions propagate upward to induce cognitive deficits, including impaired decision making (DM).\n\nMethodsWe investigated how E/I perturbations may impair temporal integration of evidence during perceptual DM in a biophysically-based model of association cortical microcircuits. Using multiple psychophysical task paradigms, we characterized effects of NMDA receptor hypofunction at two key synaptic sites: inhibitory interneurons (elevating E/I ratio, via disinhibition), versus excitatory pyramidal neurons (lowering E/I ratio).\n\nResultsDisruption of E/I balance in either direction can similarly impair DM as assessed by psychometric performance, following inverted-U dependence. Nonetheless, these regimes make dissociable predictions for task paradigms that characterize the time course of evidence accumulation. Under elevated E/I ratio, DM is impulsive: evidence early in time is weighted much more than late evidence. In contrast, under lowered E/I ratio, DM is indecisive: evidence integration and winner-take-all competition between options are weakened. These effects are well captured by an extended drift-diffusion model with self-coupling.\n\nConclusionsOur findings characterize critical roles of cortical E/I balance in cognitive functions, the utility of timing-sensitive psychophysical paradigms, and relationships between circuit and psychological models. The model makes specific predictions for behavior and neural activity that are testable in humans or animals under causal manipulations of E/I balance and in disease states.

neuroscience↗