Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells

Huang, Yanhua H.; Dykes-Hoberg, Margaret; Rothstein, Jeffrey D.; Bergles, Dwight E.

doi:10.1523/jneurosci.4473-03.2004

Cited by 91 publications

(79 citation statements)

References 52 publications

(85 reference statements)

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“…Taken together, induction protocols that include CF stimulation reveal a significantly lower threshold for PF LTD in K b D bϪ/Ϫ mice than in WT controls. Table S1) and to previous observations (26); CF complex spikes were also indistinguishable between WT and K b D bϪ/Ϫ mice (Table S2). However, when a pair of stimuli separated by 50 or 100 ms was applied to a CF, the second evoked EPSC (EPSC2) was significantly larger in K b D bϪ/Ϫ animals, rendering larger PPRs (EPSC2/ EPSC1) at K b D bϪ/Ϫ CF synapses (Fig.…”

Section: Mhcisupporting

confidence: 87%

H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning

McConnell

Huang

Datwani

et al. 2009

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

110

114

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There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now known to be expressed in neurons; however, the role of classical MHCI molecules in synaptic plasticity is unknown. We report that the classical MHCI molecules, cerebellum ͉ neuronal MHC class 1 ͉ synaptic plasticity T he class I MHC (MHCI) locus encodes perhaps the most highly polymorphic gene family in natural populations (1, 2). Although MHCI was not thought to be expressed in the healthy brain, recent discoveries have reported both classical and nonclassical MHCI expression in subsets of neurons, including cerebral cortex, hippocampus (3, 4), motoneurons (5), and the mouse vomeronasal organ (6, 7). MHCI protein has been localized in neuronal dendrites and synapses (3,8), and the non-classical H2-M10 family is co-expressed with the V2R pheromone receptors (6, 7), possibly related to MHCI-binding peptides, which have been linked to social recognition (9). Initial efforts to explore the function of MHCI in the CNS and olfactory bulb used ␤2m-and/or TAP1-deficient mice, which have markedly reduced cell surface expression of many, if not all, MHCI molecules (10, 11). These studies implicate neuronal MHCI in activity-dependent synaptic plasticity in visual and hippocampal circuits (4,8). Additional studies of ␤2m Ϫ/Ϫ mice have revealed that the stability of inhibitory synapses onto spinal motor neurons is altered after axotomy (12), and these mice also have defects in pheromone receptor localization and male-male aggressive behavior (7). Initial studies provided support-albeit indirectly-for the idea that neural MHCI molecules have nervous system functions in behavior and plasticity. To obtain direct evidence, studies of mice lacking specific MHCI molecules are needed. Here we report that Purkinje cells (PCs) co-express H2-K b and H2-D b , the 2 classical MHCI molecules in C57BL/6 mice. Mice lacking both H2-K b and H2-D b (K b D bϪ/Ϫ ) have phenotypes consistent with a requirement for these specific MHCI molecules in normal cerebellar synaptic plasticity and motor learning.

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Section: Mhcisupporting

confidence: 87%

H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning

McConnell

Huang

Datwani

et al. 2009

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

110

114

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“…Purkinje neurons, unlike O-LM interneurons, express high levels of EAAT4, and recent studies indicate that EAAT4 is responsible for the postsynaptic transporter currents recorded from Purkinje neurons (Huang et al, 2004). These studies, and the present results, suggest that EAAC1 contributes little to perisynaptic clearance at these two excitatory synapses.…”

Section: Regulation Of Mglur1 Activation By Glial Glutamate Transporterssupporting

confidence: 71%

Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

Huang¹,

Sinha²,

Tanaka³

et al. 2004

J. Neurosci.

Self Cite

152

126

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Clearance of extracellular glutamate is essential for limiting the activity of metabotropic glutamate receptors (mGluRs) at excitatory synapses; however, the relative contribution of transporters found in neuronal and glial membranes to this uptake is poorly understood. Hippocampal interneurons located at the oriens-alveus border express mGluR1␣, a metabotropic glutamate receptor that regulates excitability and synaptic plasticity. To determine which glutamate transporters are essential for removing glutamate at these excitatory synapses, we recorded mGluR1-mediated EPSCs from oriens-lacunosum moleculare (O-LM) interneurons in acute hippocampal slices. Stimulation in stratum oriens reliably elicited a slow mGluR1-mediated current in O-LM interneurons if they were briefly depolarized to allow Ca 2ϩ entry before stimulation. Selective inhibition of GLT-1 [for glutamate transporter; EAAT2 (for excitatory amino acid transporter)] with dihydrokainate increased the amplitude of these responses approximately threefold, indicating that these transporters compete with mGluRs for synaptically released glutamate. However, inhibition of all glutamate transporters with TBOA (DL-threo-bbenzyloxyaspartic acid) increased mGluR1 EPSCs Ͼ15-fold, indicating that additional transporters also shape activation of these receptors. To identify these transporters, we examined mGluR1 EPSCs in mice lacking GLAST (for glutamate-aspartate transporter; EAAT1) or EAAC1 (for excitatory amino acid carrier; EAAT3). A comparison of responses recorded from wild-type and transporter knock-out mice revealed that the astroglial glutamate transporters GLT-1 and GLAST, but not the neuronal transporter EAAC1, restrict activation of mGluRs in O-LM interneurons. Transporter-dependent potentiation of mGluR1 EPSCs led to a dramatic increase in interneuron firing and enhanced inhibition of CA1 pyramidal neurons, suggesting that acute or prolonged disruption of transporter activity could lead to changes in network activity as a result of enhanced interneuron excitability.

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“…In contrast, the PPR of KA-EPSCs was lower than that of AMPA-EPSCs at climbing fiber-Purkinje cell synapses (Huang et al, 2004), and KA-EPSCs were reduced to a greater degree when the release probability was lowered, suggesting that kainate receptors had a lower receptor occupancy than AMPA receptors at these cerebellar synapses. In our study, stimulation of mossy fibers at 0.2 Hz facilitated both types of synaptic currents to approximately equivalent degrees (ϳ190%), consistent with a previous report (Castillo et al, 1997); however, potentiation of AMPA-EPSCs was significantly larger than KA-EPSCs at higher frequencies.…”

Section: Discussionmentioning

confidence: 80%

Attenuated Plasticity of Postsynaptic Kainate Receptors in Hippocampal CA3 Pyramidal Neurons

2004

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Kainate receptor-mediated components of postsynaptic currents at hippocampal mossy fiber synapses have markedly slower kinetics than currents arising from AMPA receptors. Here, we demonstrate that other aspects of kainate and AMPA receptor function at this synapse are distinct; in particular, kainate receptor currents are less sensitive to short-and long-term increases in presynaptic strength. EPSCs arising predominantly from AMPA receptors exhibited well characterized paired-pulse facilitation, frequency facilitation, and NMDA receptor-independent long-term potentiation, whereas isolated kainate receptor synaptic currents (KA-EPSCs) exhibited attenuated facilitation and long-term potentiation. In addition, KA-EPSCs varied in their sensitivity to a low-affinity competitive antagonist, suggestive of a synaptic heterogeneity greater than that of EPSCs comprised predominantly of AMPA receptors. These data suggest that the proportional contribution of AMPA and kainate receptors to ensemble synaptic currents will vary depending on the firing frequency of mossy fiber afferents. These synaptic features may be a mechanism for limiting activation of kainate receptors at mossy fiber synapses, which has been shown to be involved in seizurogenic firing of the CA3 network.

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Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells

Cited by 91 publications

References 52 publications

H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning

H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning

Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

Attenuated Plasticity of Postsynaptic Kainate Receptors in Hippocampal CA3 Pyramidal Neurons

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Climbing Fiber Activation of EAAT4 Transporters and Kainate Receptors in Cerebellar Purkinje Cells

Cited by 91 publications

References 52 publications

H2-K b and H2-D b regulate cerebellar long-term depression and limit motor learning

H2-K b and H2-D b regulate cerebellar long-term depression and limit motor learning

Astrocyte Glutamate Transporters Regulate Metabotropic Glutamate Receptor-Mediated Excitation of Hippocampal Interneurons

Attenuated Plasticity of Postsynaptic Kainate Receptors in Hippocampal CA3 Pyramidal Neurons

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H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning

H2-K ^b and H2-D ^b regulate cerebellar long-term depression and limit motor learning