Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture

Pa, Rosenberg; Arshad, Aziz; Leitner, Melanie

doi:10.1523/jneurosci.12-01-00056.1992

Cited by 240 publications

(167 citation statements)

References 27 publications

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“…First, the high-capacity glutamate (Bergles and Jahr, 1998) and GABA- (Chatton et al, 2003) uptake systems in astroglia with processes in proximity to synapses would decrease the synaptic dwell times of either glutamate or GABA released into the synapse. This alone might increase spike rates, enabling faster signaling and reducing neuronal glutamate excitotoxicity (Rosenberg et al, 1992). However, the finding that addition of glia-conditioned medium reproduced all but the glutamate-stimulated effects indicates that diffusible trophic factors released by astroglia promote the baseline increases in spike rates.…”

Section: Discussionmentioning

confidence: 99%

Added astroglia promote greater synapse density and higher activity in neuronal networks

2007

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Astroglia are known to potentiate individual synapses, but their contribution to networks is unclear.Here we examined the effect of adding either astroglia or media conditioned by astroglia on entire networks of rat hippocampal neurons cultured on microelectrode arrays. Added astroglia increased spontaneous spike rates nearly two-fold and glutamate-stimulated spiking by six-fold, with desensitization eliminated for bath addition of 25 μM glutamate. Astrocyte-conditioned medium partly mimicked the effects of added astroglia. Bursting behavior was largely unaffected by added astroglia except with added glutamate. Addition of the GABA A receptor antagonist bicuculline also increased spike rates but with more subtle differences between networks without or with added astroglia. This indicates that networks without added astroglia were inhibited greatly. In all conditions, the log-log distribution of spike rates fit well to linear distributions over three orders of magnitude. Networks with added astroglia shifted consistently toward higher spike rates. Immunostaining for GFAP revealed a linear increase with added astroglia, which also increased neuronal survival. The increased spike rates with added astroglia correlated with a 1.7-fold increase in immunoreactive synaptophysin puncta, and increases of six-fold for GABA Aβ , two-fold for NMDA-R1 and two-fold for Glu-R1 puncta, with receptor clustering that indicated synaptic scaling. Together, these results indicate that added astroglia increase the density of synapses and receptors, and facilitate higher spike rates for many elements in the network. These effects are reproduced by glia-conditioned media, with the exception of glutamate-mediated transmission.

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Section: Discussionmentioning

confidence: 99%

Added astroglia promote greater synapse density and higher activity in neuronal networks

2007

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“…Schwann cells are a source of glutamate in themselves, since previous reports showed that cultured Schwann cells secrete glutamate (Wu et al, 2005), although the significance of glutamate secretion is unknown. In the nervous system, the importance of glutamate metabolism has previously been discussed mostly in relation to excitotoxicity and/or glutamatergic neurotransmission (Rosenberg et al, 1992). In the CNS, glutamate is metabolized to glutamine only in astrocytes (Levy, 2005).…”

Section: Discussionmentioning

confidence: 99%

Proteasomal Degradation of Glutamine Synthetase Regulates Schwann Cell Differentiation

Saitoh¹,

Araki²

2010

J. Neurosci.

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Rapid saltatory nerve conduction is facilitated by myelin structure, which is composed of Schwann cells in the peripheral nervous system. Schwann cells drastically change their phenotype following peripheral nerve injury. These phenotypic changes are required for efficient degeneration/regeneration. We previously identified ZNRF1 as an E3 ubiquitin ligase containing a RING finger motif, whose expression is upregulated in the Schwann cells following nerve injury. This suggested that posttranscriptional regulation of protein expression in Schwann cells may be involved in their phenotypic changes during nerve degeneration/regeneration. Here we report the identification of glutamine synthetase (GS), an enzyme that synthesizes glutamine using glutamate and ammonia, as a substrate for E3 activity of ZNRF1 in Schwann cells. GS is known to be highly expressed in differentiated Schwann cells, but its functional significance has remained unclear. We found that during nerve degeneration/regeneration, GS expression is controlled mostly by ZNRF1-dependent proteasomal degradation. We also found that Schwann cells increase oxidative stress upon initiation of nerve degeneration, which promotes carbonylation and subsequent degradation of GS. Surprisingly, we discovered that GS expression regulates Schwann cell differentiation; i.e., increased GS expression promotes myelination via its enzymatic activity. Among the substrates and products of GS, increased glutamate concentration inhibited myelination and yet promoted Schwann cell proliferation by activating metabotropic glutamate receptor signaling. This would suggest that GS may exert its effect on Schwann cell differentiation by regulating glutamate concentration. These results indicate that the ZNRF1-GS system may play an important role in correlating Schwann cell metabolism with its differentiation.

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“…In cultures of cerebral cortical tissue from embryonic rats, 50% of neurons die within 24 h when exposed to 4 lM of glutamate for 30 min in the absence of glial glutamate uptake. The same neuronal mortality requires 205 lM of glutamate in the presence of astrocytes in the culture (Rosenberg et al 1992). Given that glutamate levels in perilymph may reach 40 lM following ischemia as noted above (Hakuba et al 1997), a requirement for glutamate uptake by the supporting cells seems eminently necessary to protect potentially glutamate-sensitive cochlear nerve cells from damage.…”

Section: Role Of Glast In Prevention Of Excitotoxicitymentioning

confidence: 94%

Distribution of the Glutamate/Aspartate Transporter GLAST in Relation to the Afferent Synapses of Outer Hair Cells in the Guinea Pig Cochlea

Furness

Hulme

Lawton

et al. 2001

JARO

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The glutamate/aspartate transporter GLAST is known to occur in the plasma membrane of supporting cells and their glialike processes around the synaptic region of inner hair cells of the mammalian cochlea. Its function there is presumably to take up glutamate following the release of this putative amino acid neuro transmitter from the inner hair cells. In this study, we have investigated whether GLAST is also associated with the outer hair cells using postembedding immunogold labeling. This is interesting because it is uncertain whether the outer hair cells have a functional synapse at which glutamate may be released. However, earlier ultrastructural studies of the afferent synapses in outer hair cells in several mammalian species have shown features normally associated with synaptic activity. These observations are con®rmed and extended here in guinea pig where these afferent synapses have presynaptic bodies, putative synaptic vesicles, and coated pits associated with them. Immunoreactivity for GLAST was found along the plasma membranes of Deiters' cells, especially around the synaptic region of the hair cell, on processes wrapped around approaching nerve ®bers. Semiquantitative analysis of the distribution of immunogold labeling of Deiters' cells con®rmed that it was densest in the region adjacent to the synapses. There was also more labeling in apical than in basal regions of the cochlea in three of the four animals examined, suggesting an association with the number of afferent synapses, which are more numerous in apical regions. Interestingly, labeling also occurred in other regions of the cell membrane away from the afferent terminals. This suggests that glutamate uptake is also required away from the immediate vicinity of synapses, perhaps as a consequence of glutamate dispersal resulting from the mechanical displacement of the cochlear partition during stimulation. Nonetheless, the particular association of GLAST with the synaptic region of the outer hair cell implies that the latter have active afferent synapses at which glutamate is released.

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Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture

Cited by 240 publications

References 27 publications

Added astroglia promote greater synapse density and higher activity in neuronal networks

Added astroglia promote greater synapse density and higher activity in neuronal networks

Proteasomal Degradation of Glutamine Synthetase Regulates Schwann Cell Differentiation

Distribution of the Glutamate/Aspartate Transporter GLAST in Relation to the Afferent Synapses of Outer Hair Cells in the Guinea Pig Cochlea

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