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 summary Astrocytes 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.