Bezerra, T. O. | 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↗