Glutamine Synthetase: Role in Neurological Disorders

Abstract

Glutamine synthetase (GS) is an ATP-dependent enzyme found in most species that synthesizes glutamine from glutamate and ammonia. In brain, GS is exclusively located in astrocytes where it serves to maintain the glutamate-glutamine cycle, as well as nitrogen metabolism. Changes in the activity of GS, as well as its gene expression, along with excitotoxicity, have been identified in a number of neurological conditions. The literature describing alterations in the activation and gene expression of GS, as well as its involvement in different neurological disorders, however, is incomplete. This review summarizes changes in GS gene expression/activity and its potential contribution to the pathogenesis of several neurological disorders, including hepatic encephalopathy, ischemia, epilepsy, Alzheimer's disease, amyotrophic lateral sclerosis, traumatic brain injury, Parkinson's disease, and astroglial neoplasms. This review also explores the possibility of targeting GS in the therapy of these conditions.

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

“…Selective deletion of oligodendrocyte GS disrupted midbrain glutamatergic synaptic transmission and cocaine-induced locomotor sensitization, a behavior that requires glutamate signaling in the midbrain. These results represent a significant departure from the canonical view of glutamate metabolism in the CNS (Jayakumar and Norenberg, 2016; Rose et al, 2013), which posits that glutamate and glutamine are exchanged solely between astrocytes and neurons.…”

“…Following synaptic release, glutamate uptake and degradation are tightly regulated to achieve temporal and spatial signaling specificity and prevent cellular excitotoxicity (Kim et al, 2011; Sattler and Rothstein, 2006; Sheldon and Robinson, 2007). Currently, astrocytes are considered the sole glial cell type that contributes to glutamate uptake and degradation in the CNS (Jayakumar and Norenberg, 2016; Liang et al, 2006; Ortinski et al, 2010; Papageorgiou et al, 2018; Schousboe et al, 2013; Schousboe, 2019; Sun et al, 2017; Tani et al, 2014; Trabelsi et al, 2017; Yuan et al, 2017), as they express high levels of glutamate transporters and glutamine synthetase (GS), an enzyme that converts glutamate into glutamine. In keeping with this view, GS is frequently used as an astrocyte-specific marker (Armbruster et al, 2016; Habbas et al, 2015; Okuda et al, 2014; Papageorgiou et al, 2018; Theofilas et al, 2017; Tong et al, 2014).…”

“…However, GS expression has also been reported in oligodendrocytes (Bernstein et al, 2014; Takasaki et al, 2010), glial cells known for producing myelin and ensheathing axons in the CNS (Pan and Chan, 2017). Although these results remain controversial (Anlauf and Derouiche, 2013; Jayakumar and Norenberg, 2016; Sun et al, 2017), it is of great physiological and clinical importance to identify all potential cellular and molecular components involved in the life cycle of glutamate. GS deletion from the brain results in neonatal death (He et al, 2010), and mutations in the GS gene produce severe neuropathology in humans (Häberle et al, 2012; Spodenkiewicz et al, 2016).…”

“…GS deletion from the brain results in neonatal death (He et al, 2010), and mutations in the GS gene produce severe neuropathology in humans (Häberle et al, 2012; Spodenkiewicz et al, 2016). Furthermore, glutamate dysregulation has been implicated in numerous pathological states, including epilepsy, stroke, and substance use disorders, as well as several neurodegenerative diseases (Jayakumar and Norenberg, 2016; Kalivas and Duffy, 1998; Reissner et al, 2015; Sheldon and Robinson, 2007; Spencer and Kalivas, 2017; van der Hel et al, 2005; Yuan et al, 2017). For these reasons, we sought to unequivocally determine whether GS is expressed by oligodendrocytes and, if so, whether oligodendrocyte GS plays a role in maintaining glutamatergic synaptic transmission.…”

Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice

“…Among the five subtypes of glutamate transporters identified in humans, two transporters, namely, EAAT1 (GLT-1 in rodents) and EAAT2 (GLAST in rodents), which are predominantly expressed in astrocytes, effectively remove the majority of glutamate from synaptic clefts. Accordingly, dysregulation of GLT-1 or GLAST leads to glutamate accumulation in the synaptic clefts, ultimately causing excitotoxic neuronal injury and death (Jayakumar and Norenberg, 2016; Karki et al, 2015; Leke and Schousboe, 2016). The results from the present study indicate that altered expression levels of GLT-1 and GLAST by Mn, and the reversing effects of VPA and NaB might be associated with dysregulation of glutamate signaling as well as excitotoxicity in the cerebral cortex and cerebellum, eventually leading to modulation of locomotor activity and motor coordination.…”