Figure 1. Summary diagram depicting the proposed simultaneity of DBS effects on axons, astrocyte-astrocyte and astrocyte-neuronal interactions.

DBS electrode is here activating one local astrocyte (blue), leading to increased intracelluar Ca²⁺, causing hypermorphism and release of gliotransmitters, resulting in increased axonal flow and synaptic transmission. This astrocyte has multiple processes, each intimately participating at specific neuronal synapses; activation at one process/micro-domain may or may not spread to others. Multiple processes are likely occurring simultaneously.

1. Secondary activation by DBS: Increased synaptic activity between axon and dendrite, with release of neurotransmitters (e.g., glutamate), is sensed by the astrocytic Gq protein-coupled receptors on a process at the tripartite synapse (such as mGluR5), resulting in an increase in intracelluar Ca²⁺. This activation can be confined to one particular micro-domain, or can be distributed throughout the astrocyte to all its processes. Each micro-domain can express different gliotransmitters particular to the synapse.
2. Increased Ca²⁺ in astrocytes evokes post synaptic slow inward currents (SICs) in nearby neurons through astrocytic glutamate release, which binds to the NR2B subunit of extrasynaptic NMDA-R and increases neuronal excitability and increases probability of neurotransmitter release from neuronal pre-synaptic terminals.
3. Ca²⁺ activation in astrocyte causes release of extra-synaptic glutamate; glutamate binds to peri-synaptic AMPA-R on pre-synaptic neuronal processes within 400 µm of axon hillock, causes influx of Ca²⁺ which broadens action potential (AP).
4. Astrocytes in clusters, co-activated and synchronized via gap junctions/hemichannels.
5. Astrocytic processes detect local synaptic activity – glutamate release – which causes a local Ca²⁺ evoked response mediated through mGluR5 activation; this leads to release of glial ATP which is is converted by ecto-ATPase into adenosine. Adenosine then acts at pre-synaptic A1 coupled P/Q-type calcium channels to incur synaptic depression while it also acts at pre-synaptic A2 coupled L-type calcium channels to incur synaptic potentiation. Relative amounts of synaptic adenosine as well as interactions between each receptor determine the balance; here potentiation is depicted. Also, activation of pre-synaptic adenosine A2A receptors increases basal synaptic transmission.
6. Different gliotransmitters can be released at other processes due to Ca²⁺ activation in astrocyte. D-serine and glutamate are released by the activated astrocyte, modulate NMDA-R activity and synaptic plasticity. Glutamate released due to DBS astrocytic activation acts on neuronal extrasynaptic NR2B/NMDA-R, causing increased neuronal excitability and probability of downstream synaptic transmission.
7. Blood vessel proximity to astrocytes – increased CBF linked to state changes of astrocyte activity; DBS induced changes in CBF and interaction with astrocytes not resolved.