Mathematical modelling of amino acid transporter fluxes in astrocytes

Todd AC, Hulme SR, Broer S and Billups B

The Australian National University, Canberra, ACT 2600.

Astrocytes in the brain are closely associated with synapses. They support neurotransmission by sequestering the released glutamate and converting it to glutamine for recycling back to presynaptic terminals. We have previously demonstrated that astrocytic glutamate sequestration via excitatory amino acid transporters (EAATs) stimulates the release of glutamine via the System N neutral amino acid transporter SNAT3. Since the released glutamine plays a vital role in resupplying the presynaptic neurotransmitter pool, it is important to know how this process is regulated to ensure a continuous supply of neurotransmitters. Therefore, the aim of our current work is to understand how the different transporters function cooperatively to control amino acid fluxes. To investigate this, we have established a mathematical model of EAAT and SNAT3 fluxes based on kinetic rate equations. Parameters for the model were determined using electrophysioloical recording and fluorescence imaging of astrocytes in rat brain slices. Using this model, we show that EAAT-mediated fluxes of amino acids and sodium stimulate SNAT3-mediated glutamine release and that modulation of the intracellular sodium concentration is the main regulator of astrocytic glutamine efflux. Our results provide a clear demonstration of how these two transporters interact to regulate the release of amino acids from astrocytes. The model we have employed can be extended to include multiple simultaneous transport processes, and we will develop it further to understand how different plasma membrane transporters coordinate the homeostasis of amino acids in brain cells. This will provide significant benefit in enabling the prediction of the role of individual transporters in essential functions such as neurotransmission, cell growth and survival.