The mechanism of astrocytic calcium waves is reviewed above, and we propose that this is the initiating event of epileptic seizures because they could theoretically carry-over neuronal excitability from one set of recently activated neurons to another dormant set of neurons. Such a model would spatiotemporally synchronise the second group to fire unexpectedly and in harmonic synergy to the first set which is the neurophysiological hallmark of epileptiform spiking. Secondly, astrocytic calcium-wave signalling mediates interastrocytic excitation, which is the decisive final step prior to astrocytic glutamate release [69
], which then acts on neurons to evoke EPSPs [64
]. Therefore, we propose that blocking the astrocytic calcium wave represents a proximal, albeit relatively unexplored, drug target for the treatment of focal epilepsy.
From analysis of the models of astrocytic calcium-wave signalling, two obvious drug targets are apparent—gap junctions and P2Y receptors. The role of gap-junction signalling in epilepsy is still unclear [70
]. While inhibiting gap-junction signalling has already been shown to have antiepileptic properties [71
], there is evidence that ionic conductance through gap junctions only partly accounts for ionic buffering [73
]. However, the gap-junction protein Cx43 has been shown to modulate both astrocytic P2Y1 receptor expression levels [74
] and pharmacological function [75
]. Moreover, ATP efflux from Cx43 hemichannels has recently been demonstrated [76
], further expanding the scope of purinergic signalling in gliotransmission. Therefore, the role of gap junctions in propagating the calcium wave, their interplay with P2 receptors, and whether this is the substrate of their antiepileptic effect when inhibited, remains to be fully determined. In the interim, purinergic receptor modulation may hold promise in novel antiepileptic drugs indicated for focal or drug resistant epilepsy.
Moreover, we believe astrocytic purinergic signalling has a more significant role in influencing the synaptic plasticity which perpetuates epilepsy, since ATP is co-released with glutamate in a neuronal activity-dependent manner [77
]. We hypothesize that increased extracellular ATP levels promote organisation of neurons into functional assemblies, especially since ATP has been shown to do the same in development prior to synaptogenesis [78
]. This takes prominence since altered synaptic plasticity is believed to lead to neuronal circuits which are strengthened by long-term potentiation-like mechanisms [79
], and although preventing synaptic remodelling in epilepsy is a relatively unexplored area, we believe our proposed therapy will decrease long-term remodelling in the epileptic brain. Moreover, since P2 receptor activation is associated with astrogliosis [80
], P2 receptor inhibition would be expected to prevent the formation of an epileptogenic focus after brain injury.
Glial calcium waves do, however, represent a complex target owing to a variety of direct and indirect functions. Firstly, calcium-wave signalling underlies glial regulation of cerebral microvasculature and metabolism which may be either proepileptic or antiepileptic [81
]. Secondly, calcium-wave signalling may occur either as a cause or an effect of neurotransmission, and a successful antiepileptic strategy would entail targeting only those with a putatively causal role in excitatory neurotransmission. Another source of complexity is the variation in models of calcium-wave signalling (reviewed in [83
]), whose underlying mechanisms differ between brain regions. Haas et al. [84
] elegantly showed that activity-dependent ATP release propagates within mouse neocortex independent from astrocytic calcium waves, thereby raising the possibility that calcium-wave signalling may have further anatomical variations. However, this is not necessarily a setback as such variation may offer greater specificity in treating different types of seizures as specific anatomical or pharmacological targets are identified.
Taken together, it can be argued that the effects of attenuating glial calcium waves on neuronal networks in the human brain may be hard to predict. However, we argue that the same can be said of inhibiting neuronal firing en masse as a therapeutic strategy in epilepsy. The multitude of functional roles and anatomical variation of gliotransmission is analogous to the nonspecific anatomical and functional variations of neurotransmission (e.g. excitatory versus inhibitory neurotransmission, reductio ad absurdum). In other words, as more is learned about the molecular pathophysiology of the PDS, we simply offer modulation of gliotransmission as an adjunct to inhibiting neurotransmission as a novel antiepileptic approach.