ABSTRACT
INTRODUCTIONThe therapeutic success of deep brain stimulation (DBS) for movement disorders has led to its consideration for a rapidly expanding set of neurologic and psychiatric conditions-from obsessive compulsive disorder to depression and memory loss. This pressure to expand DBS applications makes it critical that all potential underlying molecular and physiologic processes that bear on its therapeutic action be investigated.To date, research has understandably focused on neuronal changes. As mentioned in the previous chapter, DBS was initially thought to silence pathologically hyperactive neurons [1-3]. Technical advances then generated the theory that DBS directly inhibits neuronal elements close to the stimulation site and elicits axonal activation and neurotransmitter release [4-11]. Mathematical models suggested that because of the dissimilar
excitability of neural elements, both soma inhibition and axonal activation can be expected at the DBS electrode site [6, 12]. None of these theories, however, address the role of astrocytes, which are more numerous than neurons and are known to make important contributions to neurotransmission, chemical homeostasis, synaptic plasticity, and control of blood flow [10, 13-16].Forming a tripartite synapse with neuronal synapses, astrocytes are active players in neural signaling [17, 18]. In addition, they respond to high-frequency stimulation (HFS) by altering important regulators of neuronal network activity and inducing release of glutamate, ATP, and adenosine [10, 14-16, 19]. Astrocytes can modify extracellular neurotransmitter concentrations, which in turn decrease pathologic neuronal oscillations [16]. While the physiological actions of astrocytes in general, and in response to HFS in particular, have been extensively investigated, little attention has been paid to their impact on therapeutic DBS. This chapter focuses on the potential role of astrocytes in DBS therapy. LocaL EffEcts of HigH-frEquEncy STIMULATION ON GLIAIt is well documented that HFS triggers propagating astrocytic Ca2+ waves [20-22]. Initial studies showed that electrical stimulation evokes long-distance Ca2+ signaling [23] and that electrical stimulation of brain tissue activates glial cells and causes increases in calcium concentration within glial cytoplasm [24]. It is also well established that local activation of glial cells can lead to a wave of activation that propagates through the glial cell syncytium in the brain for distances as great as several centimeters [24, 25]. Increases in glial calcium, in turn, evoke the release of gliotransmitters, including ATP/adenosine, glutamate, D-serine, and PGE2 [26, 27]. Release of these gliotransmitters can result in excitation or inhibition of neurons as well as the modulation of synaptic transmission and synaptic plasticity [28-31]. Astrocytic Ca2+ SignalingAstrocytes express numerous neurotransmitter receptors and respond to neuronal activity by increases in cytosolic Ca2+ [32].
