Astrocytic Receptor Systems of the Basal Ganglia

Abstract

Astrocytes are increasingly recognized as active participants of synaptic communication, yet their role in the basal ganglia circuitry remains poorly defined. Emerging evidence indicates that astrocytes in this region express a diverse array of neurotransmitter receptors thought to regulate intracellular calcium signaling, gliotransmitter release, synaptic plasticity, and neuroimmune responses. However, the literature is limited by methodological variability and a pronounced focus on the striatum, with comparatively little data on other basal ganglia nuclei. This review aims to organize the current literature on astrocytic receptor systems within the basal ganglia, including dopaminergic (D1–D5), glutamatergic (AMPA, NMDA, mGluRs), GABAergic (GABA-A, GABA-B), purinergic (P1, P2), and adrenergic (α, β) receptors. By organizing receptor-specific findings across basal ganglia structures, this review provides a foundation for future investigations into astrocytic function in this complex neural network.

1. Introduction

The basal ganglia are a group of deep cerebral nuclei implicated in the pathophysiology of various neurodegenerative and neuropsychiatric conditions [1,2]. In health, functional subdivisions and parallel processing loops allow the basal ganglia to support sensorimotor, associative, and limbic processes [3,4,5,6,7,8,9,10,11]. Accordingly, pathological changes within the basal ganglia give rise to a broad spectrum of brain-based disorders. While neurodegeneration in the various nuclei of the region is thought to trigger conditions such as Parkinson’s Disease (PD) [12], Huntington’s disease (HD) [13], multiple systems atrophy (MSA) [14], and progressive supranuclear palsy (PSP) [15], disrupted basal ganglia function has also been linked to several psychiatric conditions. Obsessive–compulsive disorder (OCD) involves altered corticostriatal connectivity within limbic circuits [16,17], while substance use disorders show both hypo- and hyperactivity in the ventral striatum [18,19,20]. Moreover, structural changes are observed in schizophrenia and bipolar disorder [21,22], and dopaminergic dysregulation within the basal ganglia is implicated in major depressive disorder (MDD) and generalized anxiety disorder (GAD) [23,24,25].

Despite extensive research across anatomical, clinical, and functional domains, our understanding of the basal ganglia circuitry remains incomplete. Key questions remain regarding their functional organization, cellular regulation, and the mechanisms driving dysfunction in neurological and psychiatric conditions. One possible bottleneck in answering these remaining questions is the lack of a clear understanding of astrocytic involvements in the basal ganglia circuitry.

While astrocytes were initially viewed as mere supportive cells, researchers have begun to appreciate their active participation in the central nervous system (CNS)’s processing [26]. The tripartite synapse model is illustrated in Figure 1 and describes CNS synaptic transmission in the context of pre- and postsynaptic neurons as well as perisynaptic astrocytic processes. Araque et al. [27] specify that astrocytes actively detect synaptic activity, release gliotransmitters and regulate the extracellular environment. Astrocytes express a diverse array of neurotransmitter receptors, including those for glutamate, GABA, dopamine, noradrenaline and purines such as ATP and adenosine. These include both fast-acting ionotropic receptors and slower-acting metabotropic G protein-coupled receptors (GPCRs) [28,29]. The effects of these receptors are multifaceted, ranging from inducing morphological changes to triggering intracellular excitability through calcium signaling [30,31,32]. Although astrocytes do not depolarize like neurons, they respond to synaptic activity with transient elevations in intracellular Ca²⁺ concentration [33]. While minimal input typically induces rapid localized Ca²⁺ responses confined to astrocytic microdomains, more intense neuronal activity can evoke slower Ca²⁺ events in the soma [34,35,36]. It has been proposed that somatic Ca²⁺ signals reflect the integration of activity from multiple synaptic inputs [34,37]. Astrocytes form functionally interconnected networks with individual astrocytes contacting as many as 100,000 synapses [38,39,40]. These synapses can be independently regulated though the synapse-specific release of gliotransmitters but also allow for the integrated coordination of neurons and astrocytes [38,41,42,43,44]. Ultimately, astrocytes influence synapse turnover, neuroinflammatory responses and the neural microenvironment [45,46,47,48,49].

Astrocytes also seem to be involved in the pathogenesis and pathophysiology of various CNS disorders [50,51]. Indeed, the loss of normal astrocyte functioning may be a primary driver of neurodegeneration [52,53]. Animal models of HD suggest a causal role of enhanced astrocytic calcium release [54], while a loss of astrocytic GABA release might be responsible for the tonic inhibition of striatal neurons in HD [55]. In Parkinson’s disease, α-synuclein has been linked to astrocyte dysfunction, triggering the release of proinflammatory cytokines and chemokines [56]. Moreover, mutations or deletions in the DJ-1 gene, which are known to cause a rare form of autosomal recessive parkinsonism [57], have been shown to exert neuroprotective effects through an astrocyte-mediated mechanism [58]. Studies on MDD consistently report a reduction in astroglial density [59], and emerging evidence suggests that the therapeutic effects of antidepressants may depend on modifying of astrocytic function, potentially reversing the glial deficits commonly observed in MDD patients [60,61]. Molecular and functional abnormalities of astrocytes have also been reported in schizophrenia and seem to critically affect the pathogenesis through neurodevelopmental and homeostatic processes [50]. Recent evidence points to a central role for astrocytes in OCD, implicating dysfunctions in their regulation of glutamate and GABA homeostasis [62,63,64,65].

Given the emerging role of astrocytes in pathophysiology and healthy brain function, the cells involvements in the basal ganglia circuitry should be thoroughly investigated. The region’s intricate connectivity indicates that astrocytes may contribute substantially to circuit homeostasis, with their mechanisms potentially contributing to complex basal ganglia motor and non-motor pathologies that are not yet fully understood. Although individual studies have examined the functional integration and receptor expression of astrocytes within this circuitry, the field still lacks a cohesive framework of astrocytic receptor systems to guide future research. To address this gap, this review aims to synthesize an overview of receptor-specific findings across the basal ganglia structures. Advancing our understanding of bidirectional interactions between neurons and astrocytes may offer key insights into the mechanisms underlying neuroinflammation, neuromodulation and synaptic transmission in health and disease. By providing a microanatomical background, this review sets the stage for future breakthroughs in theoretical understanding of the basal ganglia circuitry as well as translational applications. Astrocytic receptors might reveal novel mechanisms of intercellular communication and serve as therapeutic targets for neurological as well as neuropsychiatric disorders. The following sections will explore the basal ganglia’s most relevant astrocytic receptor systems based on the currently available literature.

2. Dopaminergic System

Dopamine receptors are GPCRs with diverse downstream effects. They can be split up into two broad categories D1-like (D₁, D₅) receptors, coupled to Gs/Golf proteins and D2-like (D₂, D₃, D₄) receptors, coupled to Gi/o proteins. Functionally, D1-like receptors are known to stimulate adenylyl cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels, the activation of protein kinase A and CREB phosphorylation [66]. D2-like receptors, on the other hand, exert opposite effects [67]. Thus, the effects of D1-like receptor stimulation are generally excitatory and those of D2-like receptor stimulation inhibitory. A wide body of literature explores the expression of dopamine receptors within the basal ganglia. While most studies are focused on the striatum, there are also reports of astrocytic dopamine receptors in the GP [68], STh [69] and SN [29,70]. Studies exploring the expression of dopaminergic receptors on basal ganglia astrocytes are listed in

Table 1. Expression of dopaminergic receptors on basal ganglia astrocytes.

Receptor	References	Brain Region(s)	Species
D1R	Miyazaki et al., 2004 [29]	Striatum, mesencephalon	Rat
	Mastrogiacomo et al., 2022 [68]	Striatum, GPe	Mouse
	Nagatomo et al., 2017 [70]	SNr	Mouse
	Reuss et al., 2000 [71]	Striatum, GP	Rat
	Zanassi et al., 1999 [72]	Striatum	Rat
D2R	Miyazaki et al., 2004 [29]	Striatum, mesencephalon	Rat
	Mastrogiacomo et al., 2022 [68]	Striatum, GPe	Mouse
	Emmi et al., 2022 [69]	STh	Human
	Reuss et al., 2000 [71]	Striatum, GP	Rat
	Shao et al., 2013 [73]	Striatum	Mouse
D3R	Miyazaki et al., 2004 [29]	Striatum, mesencephalon	Rat
	Mastrogiacomo et al., 2022 [68]	Striatum, GPe	Mouse
	Montoya et al. 2019 [74]	Striatum, mesencephalon	Mouse
	Elgueta et al., 2017 [75]	Striatum, mesencephalon	Mouse
D4R	Miyazaki et al., 2004 [29]	Striatum, mesencephalon	Rat
	Svingos et al., 1999 [76]	NAcc	Rat
D5R	Miyazaki et al., 2004 [29]	Striatum, mesencephalon	Rat
	Brito et al., 2004 [77]	Striatum	Mouse
A2A-D2R	Cervetto et al., 2017 [78]	Striatum	Rat
	Cervetto et al., 2018 [79]	Striatum	Rat
	Pelassa et al., 2019 [80]	Striatum	Rat
D2-OTR	Amato et al., 2023 [81]	Striatum	Rat
A2A-D2-OTR	Amato et al., 2024 [82]	Striatum	Rat

.

Reuss et al. [71] found no constitutive expression of D₁ receptors (D₁Rs) in striatal and mesencephalic astrocytes, however, observed an upregulation upon fibroblast growth factor 2 administration. This finding stands in contrast to other studies showing a clear expression of D₁Rs in the striatum [29,71,72] and mesencephalon [29,70]. Striatal astrocytes seem to follow the same reactivity pattern of their neuronal counterparts [70], suggesting that astrocytes might engage in the same circuit-specific signaling observed in basal ganglia neurons [83]. Interestingly, striatal D₁Rs seem to be of a different size than their neuronal counterparts [29]. In the substantia nigra reticulata (SNr), a particularly strong expression of astrocytic D₁Rs in combination with relatively weaker neuronal expression might suggest that the astrocytic receptors are the target of dendritically released dopamine [70]. In the nucleus accumbens (NAcc) of freely behaving mice and in slices, astrocytic D₁R stimulation increased intracellular Ca²⁺ concentrations, stimulated ATP/adenosine release, and depressed excitatory synaptic transmission [84].

While there was early evidence for D₂ receptor (D₂R) mRNA in the rat striatum, initial studies failed to find proof for the expression or function of astrocytic D₂R proteins [29,72]. Later, studies of synaptic suppression through astrocytes delivered functional evidence for the expression of astrocytic D₂Rs in the striatum. The preadministration of a selective D₂R agonist could prevent metabolically or chemogenetically induced depressions of striatal neurotransmission [85]. By now there is ample evidence of the presence of astrocytic D₂Rs in the human and rodent basal ganglia [29,68,69,71,73,85]. Astrocytic D₂R expression in the basal ganglia appears to be partially regulated by Dysbindin-1 (Dys1A), as Dys1A knockout mice show increased D₂R levels in the globus pallidus externus (GPe) and striatum, but not in the prefrontal cortex [68]. Shao et al. [73] observed that mice lacking astrocytic D₂Rs showed hyperreactivity to immune stimuli and a significantly increased vulnerability of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurotoxicity. The study suggests that astrocytic D₂Rs suppress neuroinflammation through an αB-crystallin-dependent mechanism. Additionally, a wide body of evidence suggests that astrocytic D₂Rs are involved in the regulation of synaptic transmission [82,85].

Similarly, Astrocytic D₃ receptors (D₃Rs) seem to play a crucial role in neuroinflammation. While the receptor is not expressed in microglia, a clustered pattern of expression was observed in astroglia [74]. Clustered patterns of expression promote the interaction of various cell-surface proteins and facilitate intracellular signaling [86]. Similarly to D₂Rs, MPTP models of Parkinson’s disease suggest that astrocytic D₃R deficiencies exacerbate inflammatory responses and neuronal loss [74,75]. Specifically, it seems likely that D₃R signaling is involved in the activation of microglia and astrocytes as well as in the regulation of the functional phenotype of microglial cells. The mechanistic and temporal details of this effect are still a topic of discussion [74,75,87,88]. While some observed a protective role of D₃R agonists in parkinsonian animals [74,88], others observed therapeutic effects of D₃R antagonists [75]. However, what does seem certain is that astrocytic D₃R dysregulation exacerbates the loss of dopaminergic neurons in the nigrostriatal pathway.

Few studies have investigated the expression of D₄ and D₅ receptors (D₄R; D₅R) in the basal ganglia. Evidence suggests that both receptors are expressed in the striatum as well as the mesencephalon [29,76,77]. Interestingly, examining all five dopamine receptor subtypes in the basal ganglia, Miyazaki et al. [29] observed the strongest immunoreactivity for D₄Rs. While investigating the developmental interaction of brain-derived neurotrophic factor (BDNF) and dopaminergic input in the neostriatum, Brito et al. [77] observed that BDNF selectively regulates astrocytic D₅Rs. This effect was not observed for D₁Rs or neuronal receptors.

Astrocytic dopamine receptors in the basal ganglia seem to engage in heteromer formations. Cervetto et al. [78,79] were the first to demonstrate receptor-receptor interactions and heteromerization of astrocytic A₂A and D₂Rs in the rat striatum. Later, these findings were confirmed by in situ proximity ligation assays (PLA). Interestingly, while almost all D₂Rs immunoprecipitated together with A₂ARs, this was only true for a fraction of A₂ARs [80]. These findings seem contradictory to Cervetto et al. ‘s [78,79] functional observation that astrocytic A₂AR activation was only consequential under D₂R coactivation. The complex down-stream interactions and functional outcomes of the receptor heteromer are excellently reviewed elsewhere [89,90], but in short, the A₂A-D₂R heteromers control the release of glutamate from striatal astrocytes. Analyses of post-mortem human tissue showed compelling early evidence for the existence of A₂A-D₂R heteromers also on astrocytes in the human STh [69]. Co-immunoprecipitation and PLA evidence suggests the heteromerization of D₂Rs also with oxytocin (OT) receptors in the rat striatum [81]. Moreover, Amato et al. [82] confirmed the existence of A₂A-D₂-OT receptor complex with ternary membrane structure. While all three receptors interact to regulate the astrocytic release of glutamate, the D₂R appears to be the main controlling factor. OT receptors seem D₂-facilitating and A₂ARs exert inhibitory control on both D₂Rs and OT receptors [78,79,81,82].

3. Glutamatergic System

Astrocytic glutamate receptors are broadly classified into two main subtypes, the ionotropic (iGluRs) and the metabotropic (mGluRs) receptors, each of which is characterized by distinct structure and signaling mechanisms that lead to different functional outcomes. Studies exploring the expression of glutamatergic receptors on basal ganglia astrocytes are listed in

Table 2. Expression of glutamatergic receptors on basal ganglia astrocytes.

Receptor	References	Brain Region(s)	Species
NMDA	Min & Nevian, 2012 [28]	Cortico-striatal synapses	Mouse
	Pascual et al., 2005 [41]	Basal ganglia (general)	Rat
	Palygin et al., 2011 [91]	Striatum	Mouse
	Henneberger et al., 2013 [92]	Striatum	Rat
	Höft et al., 2014 [93]	Striatum, NAcc	Mouse
	Sun et al., 2021 [94]	Striatum	Mouse
	Devaraju et al., 2013 [95]	Basal ganglia (general)	Mouse
	Tawfik et al., 2010 [96]	Basal ganglia (general)	Rat
	Sheldon & Robinson, 2007 [97]	Basal ganglia (general)	Rat
Kainate	Jin & Smith, 2007 [98]	Globus Pallidus	Rat
	Cavaccini et al., 2020 [99]	Striatum	Mouse
mGluR5 (Group I)	Martín et al., 2015 [83]	Basal ganglia (general)	Mouse
	Corkrum et al., 2020 [84]	NAcc	Mouse
	Cavaccini et al., 2020 [99]	Striatum	Mouse
	Testa et al., 1995 [100]	Striatum	Rat
	Spampinato et al., 2018 [101]	Basal ganglia (general)	Mouse
mGluR3 (Group II)	D’Antoni et al., 2008 [102]	SN, GP, Striatum	Rat
	Durand et al., 2013 [103]	Striatum	Mouse
	Di Menna et al., 2025 [104]	Striatum, SN	Mouse
	Matute et al., 2006 [105]	Striatum	Rat
mGluR4/8 (Group III)	Awad et al., 2000 [106]	STh	Rat
	Corti et al., 2002 [107]
	Shen & Johnson, 2003 [108]

.

3.1. Ionotropic Glutamate Receptors

The subreceptors of Ionotropic Glutamate Receptors are ligand-gated channels where Glutamate binding directly opens the channel. The astrocytic iGluRs of the basal ganglia express NMDA receptors (NMDARs), AMPA receptors (AMPARs), and Kainate receptors (KARs), nomenclature that reflects the types of synthetic agonists that activate them. The NMDA receptors are highly permeable receptors to Ca²⁺, and their activation is dependent on glycine/D-serine, which acts as a co-agonist, allowing astrocytes to influence synaptic plasticity and excitotoxicity [109]. Studies on astrocytic NMDARs have shown that, compared to neuronal NMDARs, they rarely contain an Mg²⁺ block, which has been argued to contribute towards activation at resting membrane potentials [110]. Palygin et al. [91] have shown that astrocytic NMDARs predominantly express the subunits GluN1/GluN2B/GluN3A, which confer the reduced Mg²⁺ sensitivity and the increased Ca²⁺ permeability.

Furthermore, astrocytic processes ensheath synapses, positioning NMDARs to detect spillover glutamate that escapes synaptic reuptake by EAAT1/2 transporters [111,112]. When high-frequency neuronal activity occurs, synaptic glutamate spills over to perisynaptic zones, leading to activation of the astrocytic NMDARs and hence triggering Ca²⁺ influx that results in release of gliotransmitters (e.g., ATP, D-serine) that regulate synaptic plasticity [41,92]. Studies have shown that the release of D-serine potentiates neuronal NMDARs and enhances LTP in the striatal MSNs [92], while depending on the receptor subtypes, ATP/glutamate release from the astrocytes can presynaptically inhibit or facilitate neurotransmitter release [113]. Studies of the cortico-striatal synapses show that by controlling extracellular glutamate levels, astrocytic NMDARs regulate STDP [28].

On the other hand, AMPA receptors have been found to be present in abundance in astrocytes, where unlike neurons, they express calcium-permeable AMPARs lacking the GluA2 subunit, which ensures high Ca²⁺ permeability [114,115]. As shown by Höft et al. [93], rapid transient Ca²⁺ influx in response to glutamate over-spill in the synapses is mediated by GluA1/GluA4 homomers, while Sun et al. [94] showed that striatal astrocytes present GluA2-lacking receptors, which enable Ca²-dependent gliotransmitter release. This wave-like propagation of Ca²⁺ signals through astrocytic networks facilitates long-range modulation of synaptic activity in the striatum and nucleus accumbens [93]. The regulation of AMPARs in astrocytes seems to have an activity-dependent feature, where high-frequency stimulation increases their expression on the astrocytic surface and leads to enhanced glutamate buffering in the basal ganglia system [95,96,116]. The role of the astrocytic AMPARs has been implicated further in glutamate homeostasis in the basal ganglia by expressing high-affinity excitatory amino acid transporters (EAAT1/2; GLAST/GLT-1), crucial in maintaining extracellular glutamate concentrations within physiological ranges. This feature is achieved through AMPAR-mediated depolarization of astrocytes, which increases glutamate transport via EAATs [97]. Impaired astrocytic glutamate uptake can lead to elevated extracellular glutamate levels and increased neuronal excitability, as demonstrated in studies focusing on hippocampal astrocytes [94,117]. Once glutamate is taken up by astrocytes, it is converted to glutamine and shuttled back to neurons for GABA and glutamate synthesis, completing the metabolic glutamate-glutamine cycle that maintains the excitatory/inhibitory balance in the brain [118]. Furthermore, studies show that AMPARs activation stimulates glycolysis in astrocytes and increases lactate production, serving as an energy substrate for neurons during high synaptic activity [119]. Astrocytic AMPA receptor activation can lead to ATP release, which is subsequently converted to adenosine by ectonucleotidases like CD73. This adenosine can then modulate synaptic plasticity in the striatum by acting on neuronal A₂A receptors, influencing processes such as LTD [89,120,121].

Unlike AMPAR, most Kainate receptors (KARs), except GluK1 homomers, show limited Ca²⁺ permeability [122], exhibiting rapid desensitization kinetics, with time constants in the range of a few milliseconds, which can prevent sustained depolarization during prolonged glutamate exposure [123,124]. Astrocytic KARs in the basal ganglia predominantly consist of subunits that either mediate ionotropic effects like the influx of Ca²⁺ and Na⁺ (GluK1-GluK3 *GluR5-7* subunits) or modulate receptor kinetics when coassembled (GluK4-GluK5 *KA1-2* subunits) [125]. Astrocytic glutamate transporters, particularly EAAT2, play a crucial role in maintaining extracellular glutamate homeostasis. EAAT2 is responsible for approximately 90% of glutamate uptake, effectively preventing excitotoxicity by clearing excess glutamate from the synaptic cleft. The expression of EAAT2 in astrocytes is dynamically regulated and can be upregulated in response to increased synaptic activity, thereby enhancing glutamate clearance capacity [126,127]. Furthermore, glutamate uptake by astrocytes is closely linked to their metabolic activity. The process of glutamate transport is coupled with sodium influx, which stimulates the Na⁺/K⁺-ATPase pump, leading to increased glycolytic activity within astrocytes. This metabolic shift results in the production and release of lactate, which serves as an energy substrate for neurons [128]. Although the role of KARs in astrocytic signaling within the basal ganglia remains less well defined than that of AMPARs or NMDARs, evidence suggests that KARs contribute to synaptic modulation in this region. Jin and Smith [98] demonstrated that presynaptic KAR activation in the globus pallidus reduces GABA release, pointing to a regulatory role in inhibitory transmission. While direct evidence of astrocytic KAR involvement in striatal LTD is limited, the presence of KARs in glial cells and their known ability to modulate glutamate uptake and cellular metabolism suggest a potential, yet underexplored, contribution to synaptic plasticity. Cavaccini et al. [99] demonstrated that high-frequency stimulation (HFS) leads to the activation of astrocytic metabotropic glutamate receptor 5 (mGluR5), resulting in increased intracellular calcium levels in striatal astrocytes. This calcium signaling is essential for the induction of LTD in direct-pathway MSNs. The study further revealed that this form of LTD is dependent on the activation of adenosine A₁ receptors on presynaptic terminals, suggesting that astrocyte-derived adenosine modulates glutamatergic transmission to facilitate LTD. These findings highlight a mechanism wherein astrocytic activity influences synaptic plasticity through purinergic signaling pathways [121].

3.2. Metabotropic Glutamate Receptors

The metabotropic glutamate receptors are G protein-coupled subreceptors that indirectly gate channels through the production of secondary messengers [129]. In the astrocytes of the basal ganglia, the mGluR are mostly of the subcategory of Gorup I and Group II, while Group III mGluRs are mostly found presynaptically on neurons, with some evidence for mGluR4/8 localized to perisynaptic astrocytic processes in the subthalamic nucleus playing a role in glutamate clearance [106,107,108]. These regional patterns of astrocytic mGluR expression in the basal ganglia is characteristic also for Group I mGluRs, usually found in striatal astrocytes [100], and Group II mGluRs predominantly expressed in the substantia nigra and globus pallidus [102]. During early postnatal development, astrocytic expression of group I metabotropic glutamate receptors, particularly mGluR5, is transiently elevated and plays a crucial role in synaptic maturation and glutamate homeostasis. In mice, mGluR5 expression in astrocytes peaks around postnatal day 7 and declines markedly after the second postnatal week, becoming nearly undetectable in adulthood [130]. This temporal expression pattern supports a role for astrocytic mGluR5 in the developmental tuning of corticostriatal circuits.

Functionally, activation of mGluR5 in astrocytes during this developmental period is linked to Gq protein-coupled signaling cascades, leading to increased intracellular Ca²⁺ levels [131]. These Ca²⁺ transients regulate the release of gliotransmitters and contribute to the modulation of synaptic strength and plasticity.

Moreover, mGluR5 signaling has been shown to regulate the expression and function of the glutamate transporter GLT-1 (EAAT2), enhancing glutamate clearance from the synaptic cleft and thereby maintaining extracellular glutamate concentrations within physiological limits [132]. These mechanisms are especially relevant in the basal ganglia, where astrocytic glutamate handling is critical for preventing excitotoxicity and refining synaptic signaling during early development.

Activation of astrocytic Group I mGlu5 triggers Ca²⁺ oscillations and gliotransmitter release, as shown by Cavaccini et al. [99], by application of mGluR agonist DHPG or cortical stimulation. This Ca²⁺ burst results in ATP release and conversion to adenosine, which mediates presynaptic A₁R LTD in the direct pathway synapses. On the other hand, astrocytic mGlu5 in the basal ganglia circuits have been implicated to play a role in LTP via astrocyte-mediated glutamate release acting on neuronal mGluRs [83]. This receptor also plays a role in dopamine release via P2Y1 receptors through mGluR5-driven ATP [84]. In a study by Spampinato et al. [101], the authors found that blocking astrocytic mGlu5 reduces pro-inflammatory cytokine release, such as IL-6 and IL-8, and protects neurons from excitotoxicity. A similar function has been established for Group II mGluRs, particularly mGluR3, which, by modulating and reducing cAMP levels, promotes the release of pro-inflammatory cytokines such as TNF-α in Parkinson’s disease models. This signaling pathway is implicated in neuroinflammation, a key feature in neurodegenerative diseases [102]. The neuroprotective role of mGlu3 has been further established in studies that show that mGlu3 signaling induces anti-oxidant and anti-inflammatory gene expression in striatal glia [103], while genetic loss of the receptor worsens nigrostriatal damage and microglial activation in PD models [104]. A study by Matute et al. [105] demonstrates that activation of Group II mGluRs enhances glutamate uptake by astrocytes, contributing to the prevention of excitotoxicity. This process plays a neuroprotective role by regulating glutamate levels in the striatum and other regions of the central nervous system [133].

4. GABAergic System

Early studies on GABAergic receptors done by Fraser et al. [134] showed functional ionotropic GABA-A receptors in striatal astrocytes, characterized by chloride currents. Building on this work, Lee et al. [135] confirmed the presence of subunit compositions such as α1, β2/3, in rodent models of basal ganglia astrocytes. High GABA-A receptor density, linked to tonic inhibition regulation, has been found in astrocytes in the striatum [136]. Aside from the ionotropic GABARs, studies also report the expression of metabotropic GABA-B receptors across the astrocytes of the basal ganglia, especially in the circuits involving substantia nigra and globus pallidus, where they modulate cAMP levels via Gi/o coupling and influence the dopaminergic neuronal activity [137,138]. Studies focusing on astrocyte cultures show that GABA-A receptor activation results in rapid currents and evocation of astrocytic Ca²⁺ signals by activation of voltage-gated Ca²⁺ channels, type L and T, leading to Ca²⁺ entry [139]. Such findings imply that astrocytic GABA-A receptors can utilize intracellular Ca and signaling pathways through depolarization-activated channels or indirect metabotropic cascade [140]. As shown by Liu et al. [139] GABA-A receptors are localized on astrocyte membranes, including the soma, processes, and endfeet, near synapses, suggesting their critical role in maintaining homeostasis in the nervous system. Similarly, astrocytic GABA-B receptors are mostly expressed on the somata and processes of the astrocytes [138,141]. Striatal astrocytes abundantly express GABA-B1 and GABA-B2 transcripts, where GABA-B1 protein has been detected on Aldh1L1⁺ striatal astrocytes [142]. Activation of these receptors through GABA and GABA-B agonist baclofen produces slow intracellular Ca²⁺ elevations through the IP3, evoking Ca signals [142]. Furthermore, astrocytic GABA transporters, mainly GAT-3, within BG regulate extracellular GABA and prevent over-inhibition [143,144]. As shown by Jin et al. [145] blocking astrocytic GATs leads to increase in extracellular GABA, tonically activating neuronal GABA-A and GABA-B receptors. Striatal astrocytes’ GABA uptake has been shown to significantly limit tonic GABA inhibition of dopamine release [146,147]. For example, in Parkinson’s models, dysregulated GABA uptake by striatal astrocytes through downregulation of GAT-3 is associated with reduced dopamine release and motor deficits [146]. On the other hand, astrocytic GABA-B receptors in the BG suppress glutamate release, leading to LTD in corticostriatal synapses [148].

Table 3. Expression of GABAergic receptors on basal ganglia astrocytes.

Receptor	References	Brain Region(s)	Species
GABA-α	Fraser et al., 1994 [134]	Striatum	Rat
	Lee et al., 2011 [135]	Basal ganglia (general)	Rodent
	Yoon et al., 2011 [136]	Striatum	Rat
	Liu et al., 2022 [139]	Astrocyte membranes (soma, processes, endfeet)	Rat
GABA-β	Charles et al., 2003 [138]	Substantia nigra, Globus pallidus	Rat
	Charles et al., 2003 [141]	Somata and processes of astrocytes	Rat
	Nagai et al., 2019 [142]	Striatum	Mouse
	Jin et al., 2011 [145]	Basal ganglia (general)	Rat
	Roberts et al., 2021 [146]	Striatum	Rat/Mouse
	Galvan et al., 2006 [148]	Corticostriatal synapses	Rat

presents an overview of studies that have examined the GABAergic system on basal ganglia astrocytes.

5. Purinergic System

Purinergic receptors are broadly classified into two main families based on the type of ligand they bind: P1 and P2 receptors. P1 receptors, which include A₁, A_2A, A_2B, and A₃, are GPCRs that respond to the nucleoside adenosine. A₁ and A₃ receptors (A₁R; A₃R) are primarily coupled to Gi proteins, resulting in the inhibition of adenylyl cyclase. In contrast, A_2A and A_2B receptors (A_2AR; A_2BR) couple to Gs or Golf proteins, which activate adenylyl cyclase and promote the production of cAMP. A_2BRs require significantly higher concentrations of adenosine to influence cAMP signaling but can also couple with Gq and G12 proteins [149,150]. The P2 receptor family binds primarily to adenosine triphosphate (ATP) and adenosine diphosphate (ADP) and is divided into two subtypes based on their mechanism of action [151,152]. P2X receptors (P2X₁R to P2X₇R) function as ATP-sensitive ion channels [153], whereas P2Y receptors (P2Y₁R, P2Y₂R, P2Y₄R, P2Y₆R, and P2Y₁₁R to P2Y₁₄R) are GPCRs that respond to various nucleotides including ATP and ADP [154]. Evidence for the expression of P1 and P2 receptors is listed in

Table 4. Expression of purinergic P1 receptors on basal ganglia astrocytes.

Receptor	References	Brain Region(s)	Species
A1R	Guo et al., 2024 [49]	Striatum	Mouse
	Biber et al., 1997 [155]	Striatum, tegmentum	Rat
	El-Etr et al., 1989 [156]	Striatum	Mouse, Rat
A2AR	Emmi et al., 2022 [69]	STh	Human
	Pelassa et al., 2019 [80]	Striatum	Rat
	Brambilla et al., 2003 [157]	Striatum	Rat
	Matos et al., 2013 [158]	Striatum	Mouse
	Pintor et al., 2004 [159]	Striatum	Rat
	Hettinger et al., 2001 [160]	Dorsolateral striatum	Rat
A2BR	Peakman et al., 1994 [161]	Telencephalon, diencephalon	Rat
	Vazquez et al., 2008 [162]	Striatum	Mouse
A3R	Abbracchio et al., 1998 [163]	Striatum	Rat

and

Table 5. Expression of purinergic P2 receptors on basal ganglia astrocytes.

Receptor	References	Brain Regions	Species
P2X	Franke et al., 2001 [32]	NAcc	Rat
	Franke et al., 2001 [164]	NAcc	Rat
	Franke et al., 2003 [165]	NAcc	Rat
P2Y	Centemeri et al., 1997 [30]	Striatum	Rat
	Franke et al., 2001 [32]	NAcc	Rat
	Franke et al., 2004 [164]	NAcc	Rat
	Franke et al., 2003 [165]	NAcc	Rat
	Franke et al., 2003 [166]	Striatum	Rat

, respectively.

5.1. P1 Receptor System

Astrocytic A₁Rs have been described in mouse embryonic primary astrocyte cultures and the adult brain of mice and rats [49,155,156,167]. In striatal astrocytes, they appear to modulate phospholipase C (PLC) activation. El-Etr et al. [156,167] reported that A₁Rs do not directly regulate PLC, but instead enhance noradrenaline- or carbamylcholine-induced PLC signaling by increasing extracellular glutamate and subsequently activating mGluRs. In contrast, Biber et al. [155] observed direct PLC potentiation via the Gβγ subunit of Gi/o proteins. However, this effect was not observed in striatal astrocytes where the study reports only low levels A₁R mRNA and protein expression. The discrepancy may be due to differences in the experimental models employed. Biber et al. [155] used adult rat tissue, while El-Etr et al. [167] also studied embryonic mouse striatal cultures. More recently, striatal astrocytic A₁Rs have been shown to regulate neuroinflammatory factors in response to endotoxins. While a specific ablation of astrocytic A₁Rs prevented early glial reactivity and reduced neuroinflammation, the stimulation of Gi signaling in A₁R-deficient astrocytes could restore inflammation [49].

Studies have shown the expression of A_2ARs on astrocytes in the striatum, and subthalamic nucleus and in the rodents as well as human brain [69,80,149,157,158,159,160,168,169]. In vitro studies showed that selective A_2A antagonists are able to abolish astrocytic reactivity induced by basic fibroblast growth factor (bFGF). However, they also show that A_2A agonists by itself are not sufficient to trigger astrogliosis, suggesting that A_2ARs act in concert with other bFGF-related mechanisms [157]. Basal ganglia activity is modulated by A_2ARs via glutamate-dependent mechanisms. In the short-term, astrocytic A_2ARs regulate glutamate reuptake through the modulation of Na⁺/K⁺-ATPases (NKAs) [158]. Long-term, the A_2AR triggers a cAMP pathway resulting in the decrease in both glutamate transporter 1 (GLT-I) and glutamate-aspartate transporter (GLAST) expression [168]. Moreover, the absence of astrocytic A_2ARs results in the upregulation of the NMDA-R 2B subunit and the downregulation AMPA receptors in the NAcc [169]. A_2AR antagonists prevent the effects of various glutamate uptake inhibitors that otherwise drastically increase extracellular glutamate levels [159].

Evidence on the astrocytic expression of A_2BRs in the basal ganglia is very limited but suggests that A_2BRs stimulate cAMP accumulation in primary rat astrocytes [161]. Additionally, there is evidence that A_2BRs modulate the release of interleukin-6 (IL-6) in the mouse striatum in vitro and in vivo [162]. While the increments in IL-6 concentration are likely caused by astrocytic release, the study could not exclude a neuronal origin of the cytokine [162,170].

Astrocytic A₃Rs exert dual actions on rat striatal astrocytes in culture [163,171]. At sub-threshold concentrations, selective agonists induce morphological changes characterized by stress fibres and numerous cell protrusions. While these changes proved cell-protective, the observed reduction in spontaneous apoptosis was completely counteracted by a selective A₃R antagonist. Strikingly, higher concentrations of the same agonists induced cell death in both rat astrocytes and human astrocytoma cells.

5.2. P2 Receptor Systems

Centemeri et al. [30] were the first to characterize the astrocytic Ca²⁺ response to purinergic nucleotides within the rodent striatum. Through fluorescence spectroscopy the group found that ATP induces fast and transient elevations of cytosolic Ca²⁺ levels by triggering the discharge of intracellularly stored Ca²⁺ from striatal astrocytes. The response was mediated by receptors belonging to the P2Y-receptor family and independent of ionotropic P2X-channels. In separate studies, the group around Franke et al. [164,172] found genetic evidence for the expression of all P2X receptor subtypes P2X_1-7 as well as P2Y receptor subtypes P2Y_1,2,4,6,12. However, the localization of these receptors via double immunofluorescence with receptor-specific and GFAP antibodies proved more complex. Non-injured astrocytes express P2X_2-4Rs on GFAP positive processes, with only P2X₄Rs appearing also on cell bodies. Interestingly, upon mechanical injury, P2X receptors significantly upscale their expression with P2X_2-4 subtypes expressed on astrocytic fibres and cell bodies. Moreover, a previously non-existent expression of P2X_1,5,7Rs is now evident. While P2X₁Rs and P2X₇Rs are confined to fibres and cell bodies, respectively, P2X₅Rs are expressed on both [165,172].

A similar pattern was observed for P2Y receptors. Astrocytes in the untreated rat striatum and NAcc displayed a pronounced expression of P2Y₁Rs on fibres and cell bodies [164,166]. However, showed no immunoreactivity for receptor subtypes P2Y_2,6,12, and only a weak reactivity for P2Y₄Rs confined to astrocytic fibres [164]. In contrast, four days after a mechanical injury, almost all the examined (P2Y_1,2,4,6) receptor subtypes were clearly expressed on GFAP-positive astrocytes. While P2Y₁Rs remained the dominant phenotype, a significant general upregulation was evident where only P2Y₁₂Rs remained absent. Lastly, triple-labeling for P2Y₁ and P2X₃ receptors as well as GFAP revealed the receptors’ co-expression on the same GFAP-positive astrocyte in the injured rat NAcc [164].

P2 receptors seem to regulate the astroglial response to injury in striatal tissue. While ATP analogous substances up-regulate astroglial responses to injury, P2 antagonists reduce astrocytic proliferation and furthermore, counteract the upregulation caused by ATP analogues [31]. Specifically, the mitogenic effects include the appearance of hypertrophic astrocytes, elongated and thickened astrocytic processes as well as an increase in astrocytic GFAP expression. This reaction is evident for both P2X and P2Y receptor agonists but seems stronger for P2Y agonists than P2X agonists [32,173,174]. However, reasonable uncertainties remain around the roles of specific receptor subtypes within these processes. While the involvement of P2Y₁Rs is well established [32,164], the participation of P2Y₂, P2Y₄, and P2Y₆ subtypes appears less likely [172]. The roles of P2Y₁₁, P2Y₁₂, P2Y₁₃, and P2Y₁₄ remain unclear. Although there is limited in vivo evidence of P2Y₁₂R mediated astrogliosis [32], later studies failed to detect this receptor on striatal astrocytes [164]. The astrocytic expression of P2Y₁₁, P2Y₁₃, and P2Y₁₄ receptors has not yet been studied in the basal ganglia. In terms of P2X receptors, in vivo evidence suggests the involvement of homomeric P2X_1,3Rs as well as the heteromeric P2X_4/6R in mediating astrogliosis within the NAcc [32,172]. Beyond their role in regulating astroglial responses to brain injury, P2 receptors in the basal ganglia may also influence neural adaptations associated with drug sensitization. Repeated administration of d-amphetamine (AMPH) in rats induces both behavioral sensitization and astrogliosis, along with increased expression of P2Y₁Rs on astrocytes in the striatum and nucleus accumbens. Notably, Franke et al. [166] reported that pre-treatment with a P2 receptor antagonist inhibited the development of behavioral sensitization, AMPH-induced astrogliosis, and the associated upregulation of P2Y₁R expression.

6. Adrenergic System

Similarly to the expression of adrenergic receptors on astrocytes in the cerebral cortex, studies have reported their expression in the basal ganglia [175,176]. In a study on cultured striatal astrocytes by Giaume et al. [177], the authors found expression of both α₁- and β-AR, which respond to α₁ agonists with transient Ca²⁺ elevations [178]. On the other hand, astrocytic heterogeneity is evident when compared to recent in situ RNA-seq studies that found lack of astrocytic α₁A expression in the ventral midbrain, specifically SN and the ventral tegmental area, with almost no Ca²⁺ responses to norepinephrine [179]. However, β- and α₂-ARs may still be expressed by astrocytes of the SN, but their functional role in this region is unclear.

Furthermore, autoradiographic studies show that striatal astrocytes carry α₁- and β-adrenoceptors [180], which in cultures exhibit norepinephrine-stimulated phosphoinositide turnover [181], while transient Ca²⁺ spikes in striatal astrocytes caused by α₁-agonists have been confirmed in functional assays [178]. Additionally, more than 85% of the astrocytes in the striatum express β-adrenoceptors, most of which are β₂ subtypes over β₁ [180]. Stimulation of astrocytic α₁-Ars in the striatum has been shown to result in enhanced glutamate uptake, indicative of their presynaptic localization [176].

However, contradictions in the literature can be found regarding β₂-AR expression on astrocytes, while some studies emphasize their role in glial energetics [182], Hertz et al. [176] argue β₂-AR expression on astrocytes to be uncertain. When it comes to α₁-AR, studies find that activation of this subreceptor reliably triggers transient intracellular Ca²⁺ elevations in astrocytes [183], increasing glycogen synthesis and mitochondrial oxidative metabolism [176], supporting energy storage during low activity. Interestingly, NE signaling can also prime astrocytes to release gliotransmitters (e.g., ATP, D-serine) that influence local circuits. For example, astrocytic NE action has been shown to modulate inhibitory networks; α₁-driven astrocyte Ca²⁺ waves can facilitate GABAergic inhibition in nearby neurons [183].

On another note, chronic exposures to drugs, such as cocaine, have been linked to disrupting astrocytic noradrenergic signaling and changes in morphology, which influence basal ganglia circuits involved in reward and addictive behaviour [175]. However, concrete links between astrocytic ARs and basal ganglia disorders await further study. An overview of the available literature on the astrocytic adrenergic receptor expression in the basal ganglia is presented in

Table 6. Expression of adrenergic receptors on basal ganglia astrocytes.

Receptor	References	Brain Region(s)	Species
α1-AR	Hertz et al., 2004 [175]	General	Review
	Giaume et al., 1991 [177]	Striatum	Rat
	Delumeau et al., 1991 [178]	Striatum	Rat
	Xin et al., 2019 [179]	Ventral midbrain (SN, VTA)	Mouse
	Shao & Sutin, 1992 [180]	Striatum	Rat
	Wahis & Holt, 2021 [183]	General	Review
	Hertz et al., 2004 [175]	General	Review
β-AR	Giaume et al., 1991 [177]	Striatum	Rat
	Shao & Sutin, 1992 [180]	Striatum	Rat
	Jensen et al., 2016 [182]	General	Mouse
α2-AR	Xin et al., 2019 [179]	SN	Mouse

.

7. Discussion

The neurophysiology of the basal ganglia is regulated by a network of astrocytic receptors, which play an active role in this region’s complex functions. The localization of these receptors varies across subregions, and emerging studies are increasingly exploring their precise roles. Most of the studies address the striatum where astrocyte processes envelop synapses and express multiple dopamine receptors (D1, D3–D5) [29], as well as glutamate receptors and transporters, GABA_A and GABA_B receptors [139], adenosine A_1/A_2A receptors, and adrenergic receptors (α_1A, α_2A, β_1) [176]. On the other hand, studies on the substantia nigra show exceptionally strong immunoreactivity for the D1R [70]. High expression of GABA transporter GAT-3 to clear GABA has been found in the GPe [184], participating in the circuit control. Here, the astrocytic GAT3 expression dynamically changes with behavior: increased GAT3 during habitual learning was necessary for astrocyte-driven shifts toward goal-directed behavior. On the other hand, the subthalamic nucleus is gaining more interest in research, where high-frequency stimulation in PD models modulates astrocytic NF-κB signaling and cytokine release in GP, linking astrocyte activation to improved motor outcomes [185]. Furthermore, astrocytic receptors often interact with each other and with neuronal signaling. For example, A2A–D2 heteromer in striatal astrocyte processes co-localizes and physically interact [80]. In addition, astrocytic D1R engagement may couple to cAMP or Ca²⁺, but its impact on astrocyte physiology is unknown. Similarly, metabotropic GABA_B activation clearly raises astrocytic Ca^2+, but how this shapes BG network activity is yet unclear. Another evident gap that remains in the literature is considering the subpopulations of astrocytes. Satellite astrocytes near cholinergic interneurons of the BG may have distinct receptors influencing network activity [186]. Also underexplored remain the dynamics of receptor interactions, in particular heteromer formation and anatomical distribution. Finally, the physiology of downstream pathways such as IP_3/Ca^2+, cAMP/PKA, NF-κB, glycogen metabolism, linking receptor activity to astrocytic output, remains to be detailed.

While we have focused on the most extensively studied astrocytic receptors within the BG-dopaminergic, glutamatergic, GABAergic, purinergic, and adrenergic—this review acknowledges that numerous receptor families remain insufficiently explored. For example, notably absent from this review are astrocytic endocannabinoid receptors (CB), which play a critical role in BG physiology. Although neuronal CB1 receptors have been extensively investigated in modulating synaptic plasticity, astrocytic expression and function of cannabinoid receptors are less understood and often context-dependent [187,188,189]. Similarly, serotonin, acetylcholine, and histamine receptors expressed on astrocytes may influence BG function [190,191,192], but detailed studies in this area are sparse. These underexplored receptor systems offer opportunities for future studies, especially in understanding how diverse astrocytic receptors may coordinate to modulate BG output.

Furthermore, the study of astrocytic receptor function in the BG is met with several technical and conceptual challenges. One major limitation is the heterogeneity of astrocyte populations, both across and within basal ganglia nuclei [193]. Receptor expression can vary significantly depending on the developmental stage, disease state, and even local microenvironment [194]. Additionally, differentiating astrocyte-specific receptor function from neuronal counterparts remains difficult without highly selective tools [195]. Conventional pharmacological methods often lack the precision needed to isolate astrocytic effects. [196]. Recent technological advances such as the use of astrocyte-specific viral vectors, genetically encoded calcium indicators, and cell-type-specific optogenetic, offer some promising potential [197,198,199,200].

Looking forward, future studies should aim to clarify how astrocytic receptors shape local circuit computations and behavioral outputs, particularly in disease contexts such as Parkinson’s and Huntington’s disease. Investigating the dynamic regulation of astrocytic receptor expression and signaling in response to dopaminergic or glutamatergic dysfunctions may reveal new avenues for therapeutic targets. Furthermore, understanding how astrocytes coordinate with microglia and endothelial cells to maintain homeostasis in basal ganglia networks remains a key area of interest.

8. Conclusions

In conclusion, astrocytic receptors are indispensable components of basal ganglia circuitry. Despite significant advances, much remains to be understood about their cell-type specificity, functional roles, and contributions to disease. A more integrative approach, that builds upon incorporating of molecular, cellular, and network-level analyses, could be essential in unlocking the full potential of astrocytic signaling in the basal ganglia.