System A Transporter SAT2 Mediates Replenishment of Dendritic Glutamate Pools Controlling Retrograde Signaling by Glutamate

Jenstad, Monica; Quazi, Abrar Z.; Zilberter, Misha; Haglerød, Camilla; Berghuis, Paul; Saddique, Navida; Goiny, Michel; Buntup, Doungjai; Davanger, Svend; Haug, Finn Mogens; Barnes, Carol A.; McNaughton, Bruce L.; Ottersen, Ole Petter; Storm‐Mathisen, Jon; Harkany, Tibor; Chaudhry, Farrukh A.

doi:10.1093/cercor/bhn151

Cited by 80 publications

(76 citation statements)

References 102 publications

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“…23 Glutamine synthesis can be inhibited by MSO, 24 and Gln transport can be blocked with MeAIB. 25 If the depressive behaviours caused by astrocyte ablation are due to lack of Gln supply from astroglia, inhibition of Gln synthesis in the PLC would be sufficient to evoke depressive behaviours.…”

Section: Blockade Of Gln Synthesis and Transport Increased The Duratimentioning

confidence: 99%

Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Lee

Son

Kim

et al. 2013

J Psychiatry Neurosci

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IntroductionDepression is the most common psychiatric illness, with about 121 million people affected worldwide. Of people who experience a depressive episode, 15% commit suicide.1,2 Although many studies have investigated the pathophysiologic mechanisms of major depressive disorder (MDD) using live brain imaging and postmortem studies, its etiology remains unclear; however, recent progress based on those studies has gradually revealed common features of MDD. Among these features, volume reduction of selective brain regions in patients with MDD is the most remarkable.3-5 This is mainly due to a lower number of glial cells and neuronal atrophy in those regions. 6,7 Specifically, the reduction of astrocytes among all glial cells was frequently found in postmortem studies. 3,[8][9][10] Another study reported lower levels of glutamine synthetase (GS), one of the astrocyte-specific enzymes involved in the glutamate-glutamine (Glu-Gln) cycle, and its activity levels were decreased in some clinical studies of MDD. 11A variety of preclinical studies have reported findings to support the idea of astrocyte loss and Glu-Gln disruption. Consistent with those studies, several papers have reported decreased gliogenesis and number of astrocytes in the medial prefrontal cortex (mPFC) in animal models of chronic stressinduced depression.7,12-14 These results strongly suggest that a relationship exists between the functions of astrocytes and the behavioural aspects of MDD. To test this issue, a recent study ablated astrocytes in the prelimbic cortex (PLC) using a specific toxin and revealed that depressive-like behaviours could be evoked using only this treatment.14 It remains to be determined how astrocyte loss results in depressive behaviours.To address this question, we focused on the role of astrocytes Background: The brain levels of glutamate (Glu) and glutamine (Gln) are partially regulated through the Glu-Gln cycle. Astrocytes play a role in regulating the Glu-Gln cycle, and loss of astrocytes has been associated with depressive disorders. We hypothesized that levels of Glu and Gln would be affected by astrocyte loss and dysregulation of the Glu-Gln cycle and that depressive-like behaviours would be closely related to the level of changes in Glu and Gln. Methods: We used liquid chromatography to measure Glu and Gln concentrations in the prefrontal cortex of male mice infused with L-α aminoadipic acid (L-AAA), a specific astrocyte toxin, in the prelimbic cortex. Methionine sulfoximine, a Gln synthetase inhibitor, and α-methyl-amino-isobutyric acid, a blocker of neuronal Gln transporters, were used to disturb the Glu-Gln cycle. We assessed the behavioural change by drug infusion using the forced swim test (FST) and sucrose preference test. Results: The Glu and Gln levels were decreased on the fifth day after L-AAA infusion, and the infused mice showed longer durations of immobility in the FST and lower sucrose preference, indicative of depressive-like behaviour. Mice in which Gln synthetase or Gln transport were inhibited al...

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Section: Blockade Of Gln Synthesis and Transport Increased The Duratimentioning

confidence: 99%

Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Lee

Son

Kim

et al. 2013

J Psychiatry Neurosci

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“…Indeed, glial cells are enriched with G-protein-coupled receptors, and their activation by glutamate, GABA, or other neurotransmitters are important endogenous triggers of PKC activation (Beckman et al, 1999). Complementary expression of both system A and non-system A transporters has been demonstrated on neurons, and it has been shown that the availability of glutamine regulates generation of the fast neurotransmitters (Rae et al, 2003;Jenstad et al, 2009;Solbu et al, 2010;Tani et al, 2010) and shapes the quantal size Liang et al, 2006;Fricke et al, 2007). Thus, SN1 may represent a key target for regulation of the glutamate/GABA-glutamine cycle (Fig.…”

Section: Functional Implications Of Sn1 Phosphorylationmentioning

confidence: 99%

“…According to the prevailing hypothesis, a significant amount of released glutamate and GABA is transported into perisynaptic astroglial processes, converted to glutamine, and then transported back to neurons for transmitter regeneration (Albrecht et al, 2007). Existence of such a glutamate/GABA-glutamine cycle has been bolstered by the characterization of a family of system A and system N transporters: SAT1 (Slc38a1) and SAT2 (Slc38a2) are selectively enriched in GABAergic and glutamatergic neurons, respectively, and inhibition of system A transport inhibits neuronal transmitter generation and synaptic transmission Liang et al, 2006;Jenstad et al, 2009;Solbu et al, 2010). System N transporter SN1, selectively expressed on astroglial processes ensheathing synapses, mediates release of glutamine and furnishes neurons with the primary neurotransmitter precursor (Chaudhry et al, 1999(Chaudhry et al, , 2001Boulland et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Nissen‐Meyer¹,

Popescu²,

Hamdani³

et al. 2011

J. Neurosci.

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Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase C␣ (PKC␣) and PKC␥. Electrophysiological characterization shows that phosphorylation reduces V max dramatically, whereas no significant effects are seen on the K m . Phosphorylation occurs specifically at a single serine residue (S52) in the N-terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity.

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“…SAT1 is expressed in the somatodendrites of neurons in brain regions enriched in GABAergic neurons, and its proximity to VGAT, the vesicular GABA transporter indicates that it might be related to glutamine uptake as a prerequisite to replenish the GABA neurotransmitter pool (Solbu et al, 2010;Varoqui et al, 2000). SAT2 is more ubiquitously expressed, being found localized mainly in somatodendrites and axons of glutamatergic neurons Jenstad et al, 2009). The importance of this transporter has been demonstrated by employing MeAIB (methylamino-iso-butyric acid), an inhibitor of system A, able to reduce glutamine uptake, which consequently diminishes the intracellular concentration of glutamate (Jenstad et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…SAT2 is more ubiquitously expressed, being found localized mainly in somatodendrites and axons of glutamatergic neurons Jenstad et al, 2009). The importance of this transporter has been demonstrated by employing MeAIB (methylamino-iso-butyric acid), an inhibitor of system A, able to reduce glutamine uptake, which consequently diminishes the intracellular concentration of glutamate (Jenstad et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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System A Transporter SAT2 Mediates Replenishment of Dendritic Glutamate Pools Controlling Retrograde Signaling by Glutamate

Cited by 80 publications

References 102 publications

Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

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