Subunit Composition of Kainate Receptors in Hippocampal Interneurons

Mulle, Christophe; Sailer, Andreas W.; Swanson, Geoffrey T.; Brana, Corinne; O’Gorman, Stephen; Bettler, Bernhard; Heinemann, Stephen F.

doi:10.1016/s0896-6273(00)00126-4

Cited by 198 publications

(207 citation statements)

References 40 publications

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“…In addition, it has also been shown that activating receptors incorporating the GluR5 subunit results in a reduction of g-aminobutyric acid (GABA) inhibitory synaptic transmission (Clarke et al, 1997), an effect that is again reversed by the administration of a GluR5-preferring antagonist. Given that kainate can still block hippocampal GABAergic transmission in GluR5 knockout mice, it would appear that the GluR5 is not the only subunit involved in kainite-mediated GABA interactions (Mulle et al, 2000), suggesting that heteromeric rather than homomeric receptors are required for this process. Projecting these data to the human cortex, the decrease in kainate receptors in schizophrenia containing the GluR5 subunit would likely affect the 'fine-tuning' of both inhibitory and excitatory synaptic transmission in the CNS.…”

Section: Discussionmentioning

confidence: 99%

Cortical Glutamatergic Markers in Schizophrenia

Scarr

Beneyto

Meador‐Woodruff

et al. 2005

Neuropsychopharmacol

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Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (po0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.

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Section: Discussionmentioning

confidence: 99%

Cortical Glutamatergic Markers in Schizophrenia

Scarr

Beneyto

Meador‐Woodruff

et al. 2005

Neuropsychopharmacol

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“…Kainate receptor agonists have been either reported to increase (26,37) or have no effect on the frequency of mIPSCs (24). We tested the effect of the Ca 2ϩ uncaging on mIPSCs recorded in the presence of 0.5 M tetrodotoxin to block action potentials.…”

Section: Modulation Of Mipscs By Astrocytic Calcium Elevationmentioning

confidence: 99%

Astrocyte-mediated activation of neuronal kainate receptors

Liu

Xu²,

Arcuino³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

195

128

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Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca 2؉ -dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca 2؉ in astrocytes, induced by uncaging Ca 2؉ , o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)͞kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-Daspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca 2؉ elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca 2؉ uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca 2؉ uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA͞kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.A strocytes have traditionally been considered to function as supporting cells in the central nervous system. During the past decade, it has become increasingly clear that they actively participate in intercellular communication in the brain (1-3). They are endowed with a variety of ion channels and receptors (4-6), and they display a form of excitability by changing the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (1-3, 7-9). Both application of neurotransmitters (1, 5, 10, 11) and electrical stimulation of neuronal pathways (12, 13) increase [Ca 2ϩ ] i in astrocytes. Thus, astrocytes sense and respond to neuronal activity by increasing [Ca 2ϩ ] i . The functional significance of this calcium signaling is still not well understood, but growing evidence suggests that it may trigger the release of glutamate and other neuroactive substances from astrocytes and thereby play a pivotal role in providing feedback to adjacent neurons and blood vessels. Such feedback can result in changes in neuronal excitability (8, 14-17), modulation of synaptic strength (18)(19)(20), an increase in neuronal [Ca 2ϩ ] i (8, 11), and a decrease in vascular tone (21).The study of astrocyte-neuron interactions is hampered by the lack of spec...

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“…KARs have two major activities: they contribute to the excitatory postsynaptic current/potential in response to glutamate and modulate the release of neurotransmitters (␥-aminobutyric acid [GABA] and glutamate) through presynaptic action. [39][40][41] Moreover, KARs are subjected to developmental and activitydependant regulation 42 and GluR6 function is modulated by protein phosphorylation. 43 GluR6 is abundantly expressed in brain regions involved in learning and memory (such as the hippocampus) as well as in motor and motivational aspects of behaviour (such as basal ganglia and the cerebellum).…”

Section: Glur6 As a Genetic Factor In Autism?mentioning

confidence: 99%

Linkage and association of the glutamate receptor 6 gene with autism

Jamain¹,

Betancur

Quach³

et al. 2002

Mol Psychiatry

285

184

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A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism. Molecular Psychiatry Molecular Psychiatry (2002) 7, 302-310.

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Subunit Composition of Kainate Receptors in Hippocampal Interneurons

Cited by 198 publications

References 40 publications

Cortical Glutamatergic Markers in Schizophrenia

Cortical Glutamatergic Markers in Schizophrenia

Astrocyte-mediated activation of neuronal kainate receptors

Linkage and association of the glutamate receptor 6 gene with autism

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