Astrocytes are abundant cells in the central nervous system (CNS) that play a crucial role in the clearance of neurotransmitters (Araque et al., 1999; Ventura and Harris, 1999), neuroplasticity, neuroinflammation, the regulation of cerebral blood flow and extracellular ionic concentrations (Anderson and Swanson, 2000; Volterra and Meldolesi, 2005). These cells release several neurotransmitters and mediators, such as glutamate, adenosine triphosphate (ATP) and adenosine, via calcium-dependent mechanisms (Perea et al., 2009). Similar to macrophages and microglia, astrocytes can be activated and assume an A1 pro-inflammatory secretion phenotype, losing the ability to prune synapses and regulate glutamatergic clearance (Liddelow et al., 2017). Astrocytes may also undergo an alternative A2 anti-inflammatory/restorer phenotype, which is associated with neuroprotective and reparative effects via the secretion of neurotrophic factors and synaptogenesis (Colombo and Farina, 2016; Jang et al., 2013; Liddelow et al., 2017). The above-described dichotomy (A1/A2), however, has been suggested to be far too simplistic and may not actually consider different cellular states (Escartin et al., 2021). Moreover, in addition to the influence of microglia-induced mediators, astrocytes may become reactive and respond to different micro-environment signals, including metabolic changes, abnormal calcium signaling, transcription and growth factors, intracellular kinases and glutamate levels (Lawrence et al., 2023). Overall, it is becoming clear that astrocytes accumulate numerous functions, and their molecular responses need to be better understood in disease states and mechanisms of neurological therapies.

Deep brain stimulation (DBS) involves the delivery of electrical stimulation to the brain parenchyma via implanted electrodes (Awan et al., 2009; Hamani et al., 2010b; Hamani and Nóbrega, 2010). While this technique is standard of care and approved for conditions such as Parkinson's disease (PD), tremor, dystonia and epilepsy, various novel applications are being investigated (Awan et al., 2009; Benabid, 2003; Hamani et al., 2010b; Hamani and Nóbrega, 2010; Pagano et al., 2022; Salanova, 2018). In treatment refractory depression, initial open label studies were extremely promising (Bergfeld et al., 2016; Bewernick et al., 2012, Bewernick et al., 2017; Dougherty et al., 2015; Fenoy et al., 2018; Holtzheimer et al., 2017; Kennedy et al., 2011; Malone et al., 2009; Mayberg, 2003; Mayberg et al., 2005; Riva-Posse et al., 2018; Schlaepfer et al., 2008, Schlaepfer et al., 2013). Unfortunately, the outcome of blinded studies comparing active versus sham stimulation did not reveal substantial differences between groups (Dougherty et al., 2015; Holtzheimer et al., 2017). Despite these results, recent studies refining the technique and assessing long-term data have consistently reported a substantial clinical improvement in patients receiving DBS (Bergfeld et al., 2016; Coenen et al., 2019; Holtzheimer et al., 2017).

In animal models, DBS delivered to targets homologous to those stimulated in the clinic has been shown to induce antidepressant-, anxiolytic- and antianhedonic-like responses in a number of preparations (Bregman et al., 2015, Bregman et al., 2018; Campos et al., 2023; Dandekar et al., 2017; Falowski et al., 2011; Furlanetti et al., 2015, Furlanetti et al., 2016; Hamani et al., 2010a, Hamani et al., 2010b, Hamani et al., 2012; Lim et al., 2015; Meng et al., 2011; Papp et al., 2019; Rummel et al., 2016; Schmuckermair et al., 2013; Schumacher et al., 2020; Thiele et al., 2018, Thiele et al., 2020; Volle et al., 2018). Proposed mechanisms for these effects include the modulation of neuronal activity, changes in receptor expression, metabolic effects and the development of neuroplasticity (e.g. neurogenesis, increase in trophic factors, synaptogenesis (for a review see (Campos et al., 2023; Hamani and Temel, 2012)). Even though astrocytes are important for synaptic and neuronal homeostasis, their role in the antidepressant-like effects of DBS remains unclear. At the high frequencies used in the clinic (e.g. >100 Hz), stimulation has been proposed to activate astrocytes and initiate astrocyte-neuronal interactions that may, at least in part, be responsible for some DBS effects (Etiévant et al., 2013; Fenoy et al., 2014; Salatino et al., 2017; Vedam-Mai et al., 2012).

In this manuscript, we review the role of astrocytes as a potential substrate for the antidepressant-like effects of DBS, particularly focusing on preclinical models.