Fig 1.
Compartmental model of tripartite glutamatergic synapse.
(1) A 10 Hz simulated spike train mimicking in vivo spontaneous activity results in a deterministic release of vesicular glutamate and voltage-dependent potassium (K+) efflux from the presynaptic neuron into the synaptic cleft: (2a) Glutamate (Glu-) activates N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the postsynaptic neuron and (2b) Metabotropic glutamate receptors (mGluRs) located on the astrocytic membrane: (3) Glu- is removed from the synaptic cleft compartment by sodium (Na+) dependent excitatory amino-acid transporters (EAATs): (4) Glu- and 3Na+ enters the astrocytic compartment, the former to be either converted to glutamine or α-ketoglutarate, or packaged into vesicles: (5) Activation of the astrocytic mGluRs results in production of inositol 1, 4, 5-trisphosphate (IP3): (6) IP3 opens Ca2+ channels on the endoplasmic reticulum (ER) allowing an efflux of Ca2+ into the cytoplasm in both the soma and perisynaptic process compartments: (7) Ca2+ elevation in the process stimulates the release of glutamate vesicles: (8) Astrocytic released glutamate binds to extrasynaptic glutamate receptors: (9) A slow inward current (SIC) is generated in the post-synaptic compartment: Astrocytic homeostatic (10a) Sodium/Potassium pump (NaK-ATPase) removes Na+ast. and K+syn (10b) Sodium-Calcium exchanger (NCX) exchanges 1Ca2+ for 3Na+ across the membrane.
Fig 2.
Development of EAAT2 model from experimental data [38].
Computational model for maximal EAAT current density as function of driving force (V-Vrev) [described in S1 Text]. (Dots: Experimental data [38], line: data fit).
Fig 3.
Presynaptic neuron-astrocyte interaction for presynaptic 10 Hz simulation (top) for different basal [Glu]ast.
(a) The synaptic glutamate concentration resulting from presynaptic release and astrocytic uptake, indicates a longer time course of glutamate in synaptic cleft where [Glu]ast is increased due to slower uptake by EAAT2. Inset: closer view of synaptic glutamate concentration. (b) Higher activation of mGluRs in response to prolonged synaptic glutamate (Inset: closer view of astrocytic mGluRs activation) resulting in (c) perturbation of IP3 production and degradation, activating Ca2+ ER channels and resulting [Ca2+] elevations in the (d) perisynaptic process. (e) The release of glutamate by astrocyte in response to super-threshold Ca2+ elevations and enhanced by increased cytosolic [Glu]. (f) Increase in astrocytic membrane potential (Vast) as a result of synaptic-driven currents.
Fig 4.
Variable astrocytic sodium ([Na+]ast) and synaptic potassium ([K+]syn) concentrations for presynaptic 10Hz simulation.
(a) [Na+]ast and (b-e) Na+ currents generated by EAAT2, NCX, NaK-ATPase & background membrane leak. (f) [K+]syn and (g-i) K+ currents generated by EAAT2, NaK-ATPase & background membrane leak. (Inset: 1 second closer view).
Fig 5.
Variable astrocytic calcium ([Ca2+]ast) concentration in the soma and perisynaptic process for presynaptic 10Hz simultation.
(a) [Ca2+]ast,soma as determined by (b-d) Sarco/endoplasmic reticulum Ca2+-ATPase SERCA pump, IP3-gated channels and ER leak fluxes, respectively, and (e) [Ca2+]ast,process dynamics as influenced by the (f-h) NCX, synaptic-driven IP3 gated channel activation and membrane leak fluxes, respectively.
Fig 6.
Stability diagram of astrocytic calcium activity in the (a) soma and (b) perisynaptic process, [Ca2+]ast, on frequency of periodic presynaptic firing activity under different baseline astrocytic level [Glu]ast,eq. (o) denotes upper and lower amplitudes of oscillation at steady state. Lower bound of induced oscillatory regime is increased with decreasing [Glu]ast,eq. Demonstrates a clear range of input presynaptic firing frequencies which result in Ca2+ activation across the three measured [Glu]ast,eq. where increasing [Glu]ast,eq correlates with reduction in the lower limit of this range.
Fig 7.
Schematic representations of the two pathways in the model.
(a) Direct pre- to post-synaptic neuron transmission only, passive astrocyte responsible for glutamate uptake (dotted line). (b) Indirect pre-to post-synaptic (via astrocyte activation) transmission only.
Fig 8.
Postsynaptic activity due to synaptic and intrinsic currents, triggered by (a) synaptic glutamate [Glu]syn (b-d) simulation with [Glu]ast,eq = 1.5mM, 5mM, and 10mM respectively, synaptic currents (Isyn) combined AMPA- and NMDA-mediated currents in response to synaptic glutamate, membrane potential (Vm) of postsynaptic neuron resulting from combination of Isyn and voltage-gated currents (Na+, K+ and leak). Prolonged time course of synaptic glutamate leads to enhanced synaptic currents (Isyn) and higher frequency postsynaptic firing response (Vm depolarisations) as [Glu]ast,eq increases.
Fig 9.
Postsynaptic membrane potential due to SIC and intrinsic currents simulation.
(a) extrasynaptic glutamate (GA) released by the astrocyte. (b-d) [Glu]ast,eq = 1.5mM, 5mM, and 10mM respectively, (right closer view of boxed area for [Glu]ast,eq = 10 mM). SIC (Isic) in each case given (above) and resulting postsynaptic membrane potential (Vm) (below). Enhanced release of astrocytic glutamate results in stronger and prolonged Isic and subsequent prolonged high-frequency postsynaptic firing (Vm depolarisations) due to increasing [Glu]ast,eq.
Fig 10.
Frequency of postsynaptic firing due to combination of synaptic, extrasynaptic and intrinsic currents.
Simulation with [Glu]ast,eq = 1.5mM, 5mM, and 10mM (left to right). (a) Frequency of postsynaptic firing due to the glutamate release both directly from the presynaptic neuron and from the astrocyte, (b) Frequency of postsynaptic firing due to synaptic glutamate-mediated currents and (c) Frequency of postsynaptic firing due to astrocytic-released-activated currents. Presynaptic activation given as (above b) bar and (above c) SIC. Frequency of postsynaptic firing was calculated using rectangular windowing of length 2 sec, 0.1 overlap. Increasing [Glu]ast,eq results in higher baseline postsynaptic firing to identical presynaptic stimuli determined by longer time course of synaptic glutamate and thus enhanced synaptic-mediated currents. Increasing [Glu]ast,eq also results in longer intervals of high (~60Hz where [Glu]ast,eq = 10mM) frequency, longer lasting postsynaptic depolarisations as a result of enhanced gliotransmission.