Chronic inhibition of glutamine synthetase is not associated with impairment of learning and memory in mice

Blin, Marion; Crusio, Wim E.; Hevor, T. K.; Cloix, Jean François

doi:10.1016/s0361-9230(01)00631-1

Cited by 33 publications

(33 citation statements)

References 32 publications

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“…In these mice, synaptic transmission is only impaired under intense stimulation and, even then, is not completely abrogated; although, these effects do lead to deficits in basic behavior. However, in a separate study using a spatial learning paradigm, glutamine synthetase inhibition by MSO did not decrease performance relative to control mice (Blin et al, 2002).…”

Section: Pharmacology Of Glutamate-glutamine Inhibitionmentioning

confidence: 68%

Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle

Kam¹,

Nicoll²

2007

J. Neurosci.

116

101

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The glutamate-glutamine cycle is thought to be integral in continuously replenishing the neurotransmitter pool of glutamate. Inhibiting glial transfer of glutamine to neurons leads to rapid impairment in physiological and behavioral function; however, the degree to which excitatory synaptic transmission relies on the normal operation of this cycle is unknown. In slices and cultured neurons from rat hippocampus, we enhanced the transfer of glutamine to neurons, a fundamental step in this cycle, by adding exogenous glutamine. Although raising glutamine augments synaptic transmission by increasing vesicular glutamate, access to this synthetic pathway by exogenously applied glutamine to neurons is delayed and slow, challenging mechanisms linking the rapid effects of pharmacological inhibitors to decreased vesicular glutamate. We find that pharmacological inhibitors of glutamine synthetase or system A transporters cause an acute depression of basal synaptic transmission that is rapidly reversible, which is unlikely to be attributable to the rapid loss of vesicular glutamate. Furthermore, release of vesicular glutamate remains robust even during the prolonged removal of glutamine from pure neuronal cultures. We conclude that neurons have the capacity to store or produce glutamate for long periods of time, independently of glia and the glutamate-glutamine cycle.

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Section: Pharmacology Of Glutamate-glutamine Inhibitionmentioning

confidence: 68%

Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle

Kam¹,

Nicoll²

2007

J. Neurosci.

116

101

View full text Add to dashboard Cite

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“…Rats and mice, however, tolerate much higher doses with no adverse effects [5,31]. For the experiments reported herein, we followed the dose and dosing schedule from Blin et al, [32] who showed that treating mice with 20 mg/kg three times per week did not cause seizures and had no other adverse effects on the behavior of these mice, including learning. We found that this dose did not have any apparent adverse effects on either the SOD1 G93A mice or on a cohort of wild-type mice (data not shown), similar to previously published results [32].…”

Section: Resultsmentioning

confidence: 99%

Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS

Ghoddoussi

Galloway

Jambekar

et al. 2010

Journal of the Neurological Sciences

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“…Furthermore, we could not detect a change in the immunoreactivity for the glial glutamate transporter GLT1 or see histological evidence of neuronal degeneration by light microscopy. Moreover, chronic MSO administration does not substantially reduce learning and memory behavior in mice on the radial maze test (Blin et al, 2002), and MSO can be protective in cerebral ischemia (Swanson et al, 1990). Thus, interfering with the TANIGAMI et al…”

Section: Astrocyte Swellingmentioning

confidence: 99%

Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats

et al. 2005

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Inhibition of glutamine synthesis reduces astrocyte swelling and associated physiological abnormalities during acute ammonium acetate infusion in anesthetized rats. We tested the hypothesis that inhibition of glutamine accumulation during more prolonged ammonium acetate infusion in unanesthetized rats reduces cortical astrocyte swelling and immunohistochemical changes in astrocytic proteins. Rats received a continuous i.v. infusion of either sodium acetate or ammonium acetate for 24 h to increase plasma ammonia from about 30-400 μmol/l. Cohorts were pretreated with vehicle or L-methionine-S-sulfoximine (MSO; 0.83 mmol/kg). MSO reduced glutamine synthetase activity by 57% and glutamine synthetase immunopositive cell number by 69%, and attenuated cortical glutamine accumulation by 71%. Hyperammonemia increased the number of swollen astrocytes in cortex and MSO reduced this increase to control values. The number of glial fibrillary acidic protein immunopositive cells in cortex was greater in hyperammonemic rats and the increase in superficial cortical layers was attenuated by MSO. Immunoreactivity for the gap junction protein connexin-43 in the neuropil, assessed by optical density, was greater in the hyperammonemic group compared with controls, but this increase was not attenuated by MSO. No changes in the optical density of GLT1 glutamate transporter immunoreactivity in cortex were detected in any group. We conclude that glutamine synthetase inhibition reduces astrocyte swelling and ameliorates some of the reactive astroglial cytoskeletal alterations seen at 24 h of hyperammonemia, but that gap junction changes in astrocytes occur independently of glutamine accumulation and swelling. Keywords ammonia; astrocyte; connexin; cerebral edema; glial fibrillary acidic protein; glutamine Astrocyte swelling is a distinctive feature of the histological finding in humans who die from severe liver disease or urea cycle disorders. Experimental models of liver dysfunction and hyperammonemia are also marked by watery swelling of astrocytes and cellular hypertrophy of astrocyte cell bodies without necessarily presenting with overt neuronal pathology. Thus, hyperammonemia is considered to be a major factor contributing to the cellular changes seen in severe hepatic encephalopathy (Norenberg, 1998 Tracer studies reveal that blood-borne ammonia is rapidly incorporated into brain glutamine, and that this process is markedly slowed in vivo by inhibiting glutamine synthetase (GS) with methionine sulfoximine (MSO), thereby disrupting compartmentation of nitrogen metabolism (Cooper et al., 1979). Based on the observations 1) that increased brain glutamine concentration is one of the most consistent biochemical change seen both clinically and experimentally with liver disease, urea cycle disorders or pure hyperammonemia (Cooper, 2001), and 2) that GS is enriched in astrocytes (Norenberg and Martinez-Hernandez, 1979), we postulated that glutamine accumulated in astrocytes may act as an osmolyte that contributes to astrocyte swelli...

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Chronic inhibition of glutamine synthetase is not associated with impairment of learning and memory in mice

Cited by 33 publications

References 32 publications

Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle

Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle

Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS

Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats

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