EAAT1 and d-serine expression are early features of human retinal development

Diaz, Claudia M.; Macnab, L. T.; Williams, Susan M.; Sullivan, Rodney N.; Pow, David V.

doi:10.1016/j.exer.2007.01.008

Cited by 23 publications

(16 citation statements)

References 31 publications

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“…20 Our ability to detect uptake of D-aspartate into interstitial cells that express immunoreactivity for C-terminal GLAST/GLAST1a/GLAST1b suggests that these proteins may be functional transporters. The lack of detectable amino-terminal GLAST in the tissue, despite being consistently detected in brain tissues in our hands, 19,24,40,41 suggests that the amino-terminus may be modified or cleaved in the testis. Susarla et al 42 have noted that increased transport activity by GLAST can be associated with a paradoxical loss of immunoreactivity for N-and C-terminal epitopes of GLAST, a phenomenon previously noted as indicating the modification or cleavage of these regions.…”

Section: Discussionmentioning

confidence: 51%

Expression of multiple glutamate transporter splice variants in the rodent testis

Lee¹,

Anderson²,

Barnett³

et al. 2010

Asian J Androl

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Glutamate is a regulated molecule in the mammalian testis. Extracellular regulation of glutamate in the body is determined largely by the expression of plasmalemmal glutamate transporters. We have examined by PCR, western blotting and immunocytochemistry the expression of a panel of sodium-dependent plasmalemmal glutamate transporters in the rat testis. Proteins examined included: glutamate aspartate transporter (GLAST), glutamate transporter 1 (GLT1), excitatory amino acid carrier 1 (EAAC1), excitatory amino acid transporter 4 (EAAT4) and EAAT5. We demonstrate that many of the glutamate transporters in the testis are alternately spliced. GLAST is present as exon-3-and exon-9-skipping forms. GLT1 was similarly present as the alternately spliced forms GLT1b and GLT1c, whereas the abundant brain form (GLT1a) was detectable only at the mRNA level. EAAT5 was also strongly expressed, whereas EAAC1 and EAAT4 were absent. These patterns of expression were compared with the patterns of endogenous glutamate localization and with patterns of D-aspartate accumulation, as assessed by immunocytochemistry. The presence of multiple glutamate transporters in the testis, including unusually spliced forms, suggests that glutamate homeostasis may be critical in this organ. The apparent presence of many of these transporters in the testis and sperm may indicate a need for glutamate transport by such cells.

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Section: Discussionmentioning

confidence: 51%

Expression of multiple glutamate transporter splice variants in the rodent testis

Lee¹,

Anderson²,

Barnett³

et al. 2010

Asian J Androl

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“…Müller glial cells have established roles in the maintenance of retinal neurons via their regulation of glutamate neurotransmitter levels and their expression of neurotrophic factors (Fields and Stevens-Graham, 2002; Newman, 2004; de Melo Reis et al, 2008). Although a role for Müller glia in retinal synaptogenesis has been suggested by several studies (Georges et al, 2006; Diaz et al, 2007), little is known about how this putative function might be accomplished. In the brain, glutamate receptor function has been shown to be important for synaptogenesis (Han and Stevens, 2009; Kakegawa et al, 2009), so glutamate uptake by Müller cells might similarly be important for synaptic development of photoreceptors.…”

Section: Discussionmentioning

confidence: 99%

Harmonin (Ush1c) is required in zebrafish Müller glial cells for photoreceptor synaptic development and function

Phillips

Blanco-Sánchez

Lentz

et al. 2011

Disease Models &Amp; Mechanisms

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SUMMARYUsher syndrome is the most prevalent cause of hereditary deaf-blindness, characterized by congenital sensorineural hearing impairment and progressive photoreceptor degeneration beginning in childhood or adolescence. Diagnosis and management of this disease are complex, and the molecular changes underlying sensory cell impairment remain poorly understood. Here we characterize two zebrafish models for a severe form of Usher syndrome, Usher syndrome type 1C (USH1C): one model is a mutant with a newly identified ush1c nonsense mutation, and the other is a morpholino knockdown of ush1c. Both have defects in hearing, balance and visual function from the first week of life. Histological analyses reveal specific defects in sensory cell structure that are consistent with these behavioral phenotypes and could implicate Müller glia in the retinal pathology of Usher syndrome. This study shows that visual defects associated with loss of ush1c function in zebrafish can be detected from the onset of vision, and thus could be applicable to early diagnosis for USH1C patients.

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“…At the initial phase of synapse formation in hippocampus, neurons only express NMDARs, which must be activated for AMPARs to be delivered to synapses (Durand et al 1996), and adult SRKO mice have shown elevated expression of NMDAR subunits in the postsynaptic density of hippocampal neurons (Balu & Coyle, 2011). In the retina, d‐ serine is present in Müller cells prior to the expression of synaptic proteins (Diaz et al 2007) where it might serve a role in synaptogenesis. If d‐ serine is important in driving AMPAR insertion in retinal synapses, then one might expect to find an increase in the NMDA/AMPA ratio, the opposite of what we observed.…”

Section: Discussionmentioning

confidence: 99%

Serine racemase deletion abolishes light‐evoked NMDA receptor currents in retinal ganglion cells

Sullivan

Esguerra

Wickham

et al. 2011

The Journal of Physiology

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Non-technical summary Retinal ganglion cells represent a population of neurons that relay information from the retina to the brain. During retinal light responses, the spiking activity of retinal ganglion cells is shaped in part by NMDA receptors, which require a coagonist for activation. There is debate over if glycine or D-serine serves as the endogenous coagonist to retinal ganglion cell NMDA receptors. To address this question, we used a mutant mouse lacking functional serine racemase, the D-serine-synthesizing enzyme. In this study we show that D-serine is required to activate retinal ganglion cell NMDA receptors during light stimulation. Mice lacking serine racemase also appeared to have alterations in the relative contribution of NMDA and AMPA receptors to light responses. Interestingly, behavioural tests showed that mice lacking serine racemase had no apparent visual deficits. Collectively, these findings raise interesting questions about the role of D-serine in shaping excitatory synapses and in visual processing. AbstractGlycine and/or D-serine are obligatory coagonists of the N -methyl-D-aspartate receptor (NMDAR). Serine racemase, the D-serine-synthesizing enzyme, is expressed by astrocytes and Müller cells of the retina, but little is known about its role in retinal signalling. In this study, we utilize a serine racemase knockout (SRKO) mouse to explore the contribution of D-serine to inner-retinal function. Retinal tissue levels of D-serine in SRKO mice are reduced by 85%. Whole-cell recordings from SRKO retinal ganglion cells showed markedly reduced coagonist occupancy of NMDARs and consequently a dramatic reduction in the NMDAR component of light-evoked responses. NMDAR currents in SRKOs could be rescued by applying exogenous coagonist, but SRKO ganglion cells still displayed lower NMDA/AMPA receptor ratios than wild-type (WT) controls when the coagonist site was saturated. Despite having abnormalities in synaptic glutamatergic transmission, SRKO mice displayed no obvious signs of visual impairment in behavioural testing. These findings raise interesting questions about the role of D-serine in inner-retinal function and development.

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EAAT1 and d-serine expression are early features of human retinal development

Cited by 23 publications

References 31 publications

Expression of multiple glutamate transporter splice variants in the rodent testis

Expression of multiple glutamate transporter splice variants in the rodent testis

Harmonin (Ush1c) is required in zebrafish Müller glial cells for photoreceptor synaptic development and function

Serine racemase deletion abolishes light‐evoked NMDA receptor currents in retinal ganglion cells

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