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Functional contributions of glutamate transporters at the parallel fibre to Purkinje neuron synapse-relevance for the progression of cerebellar ataxia.

Power EM, Empson RM - Cerebellum Ataxias (2014)

Bottom Line: The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse.Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output.Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Brain Health Research Centre, University of Otago School of Medical Sciences, PO Box 56, 9054 Dunedin, New Zealand.

ABSTRACT

Background: Rapid uptake of glutamate by neuronal and glial glutamate transporters (EAATs, a family of excitatory amino acid transporters) is critical for shaping synaptic responses and for preventing excitotoxicity. Two of these transporters, EAAT4 in Purkinje neurons (PN) and EAAT1 in Bergmann glia are both enriched within the cerebellum and altered in a variety of human ataxias.

Results: PN excitatory synaptic responses and firing behaviour following high frequency parallel fibre (PF) activity commonly encountered during sensory stimulation in vivo were adversely influenced by acute inhibition of glutamate transporters. In the presence of a non-transportable blocker of glutamate transporters we observed very large amplitude and duration excitatory postsynaptic currents accompanied by excessive firing of the PNs. A combination of AMPA and mGluR1, but not NMDA, type glutamate receptor activation powered the hyper-excitable PN state. The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse.

Conclusions: Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output. Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

No MeSH data available.


Related in: MedlinePlus

Inhibition of glutamate transporters enhances paired pulse facilitation at the PF-PN synapse and prolongs the decay of the excitatory post synaptic current, EPSC.A, shows an example recording from a PN showing EPSCs evoked with a pair of closely timed single stimulations to the PFs (downward arrows). Note the enhancement of the amplitude of the second EPSC upon application of 50 μM TBOA and the concomitant increase in duration of the second EPSC, in the absence of any change in the amplitude of the first EPSC (in 7/11 cells shown in A(i) where bars are mean ± SEM, ns is not significant in Student’s paired t-test). Dashed lines in A represent single exponential fits to estimate the time constant of recovery of the second EPSC; mean values (error bars are SEM) shown in A(ii) ** represents P < 0.01 Student’s paired t-test. Inset traces indicate no change in series resistance or input resistance by TBOA, see text, scale bar is 100 pA and 10 ms. B shows the change in mean absolute values of PPF in Control and after 50 μM TBOA, bars are mean ± SEM, ** represents P < 0.01 Student’s paired t-test. Left panel shows PPF change normalised to control for the 7/11 cells, bold colour, with remaining cells where the first EPSC increased, and PPF also increased, after TBOA, shown in a transparent shade.
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Fig4: Inhibition of glutamate transporters enhances paired pulse facilitation at the PF-PN synapse and prolongs the decay of the excitatory post synaptic current, EPSC.A, shows an example recording from a PN showing EPSCs evoked with a pair of closely timed single stimulations to the PFs (downward arrows). Note the enhancement of the amplitude of the second EPSC upon application of 50 μM TBOA and the concomitant increase in duration of the second EPSC, in the absence of any change in the amplitude of the first EPSC (in 7/11 cells shown in A(i) where bars are mean ± SEM, ns is not significant in Student’s paired t-test). Dashed lines in A represent single exponential fits to estimate the time constant of recovery of the second EPSC; mean values (error bars are SEM) shown in A(ii) ** represents P < 0.01 Student’s paired t-test. Inset traces indicate no change in series resistance or input resistance by TBOA, see text, scale bar is 100 pA and 10 ms. B shows the change in mean absolute values of PPF in Control and after 50 μM TBOA, bars are mean ± SEM, ** represents P < 0.01 Student’s paired t-test. Left panel shows PPF change normalised to control for the 7/11 cells, bold colour, with remaining cells where the first EPSC increased, and PPF also increased, after TBOA, shown in a transparent shade.

Mentions: As seen in Figure 4, TBOA increased PPF at the PF synapse. This result implies that excess glutamate availability reduced the probability of glutamate release at this synapse. Importantly, in 7/11 cells we observed this TBOA-enhanced PPF in the absence of any change in the amplitude of the first EPSC, as seen in Figure 4A. In the remaining 4/11 cells TBOA enhanced the 1st EPSC and PPF, shown in Figure 4A, but we excluded these cells since interpretation becomes more complex under these circumstances. Note also that TBOA prolonged the recovery of the second of the pair of EPSCs, see Figure 4A, consistent with a slowed recovery of postsynaptic glutamate clearance.Figure 4


Functional contributions of glutamate transporters at the parallel fibre to Purkinje neuron synapse-relevance for the progression of cerebellar ataxia.

Power EM, Empson RM - Cerebellum Ataxias (2014)

Inhibition of glutamate transporters enhances paired pulse facilitation at the PF-PN synapse and prolongs the decay of the excitatory post synaptic current, EPSC.A, shows an example recording from a PN showing EPSCs evoked with a pair of closely timed single stimulations to the PFs (downward arrows). Note the enhancement of the amplitude of the second EPSC upon application of 50 μM TBOA and the concomitant increase in duration of the second EPSC, in the absence of any change in the amplitude of the first EPSC (in 7/11 cells shown in A(i) where bars are mean ± SEM, ns is not significant in Student’s paired t-test). Dashed lines in A represent single exponential fits to estimate the time constant of recovery of the second EPSC; mean values (error bars are SEM) shown in A(ii) ** represents P < 0.01 Student’s paired t-test. Inset traces indicate no change in series resistance or input resistance by TBOA, see text, scale bar is 100 pA and 10 ms. B shows the change in mean absolute values of PPF in Control and after 50 μM TBOA, bars are mean ± SEM, ** represents P < 0.01 Student’s paired t-test. Left panel shows PPF change normalised to control for the 7/11 cells, bold colour, with remaining cells where the first EPSC increased, and PPF also increased, after TBOA, shown in a transparent shade.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig4: Inhibition of glutamate transporters enhances paired pulse facilitation at the PF-PN synapse and prolongs the decay of the excitatory post synaptic current, EPSC.A, shows an example recording from a PN showing EPSCs evoked with a pair of closely timed single stimulations to the PFs (downward arrows). Note the enhancement of the amplitude of the second EPSC upon application of 50 μM TBOA and the concomitant increase in duration of the second EPSC, in the absence of any change in the amplitude of the first EPSC (in 7/11 cells shown in A(i) where bars are mean ± SEM, ns is not significant in Student’s paired t-test). Dashed lines in A represent single exponential fits to estimate the time constant of recovery of the second EPSC; mean values (error bars are SEM) shown in A(ii) ** represents P < 0.01 Student’s paired t-test. Inset traces indicate no change in series resistance or input resistance by TBOA, see text, scale bar is 100 pA and 10 ms. B shows the change in mean absolute values of PPF in Control and after 50 μM TBOA, bars are mean ± SEM, ** represents P < 0.01 Student’s paired t-test. Left panel shows PPF change normalised to control for the 7/11 cells, bold colour, with remaining cells where the first EPSC increased, and PPF also increased, after TBOA, shown in a transparent shade.
Mentions: As seen in Figure 4, TBOA increased PPF at the PF synapse. This result implies that excess glutamate availability reduced the probability of glutamate release at this synapse. Importantly, in 7/11 cells we observed this TBOA-enhanced PPF in the absence of any change in the amplitude of the first EPSC, as seen in Figure 4A. In the remaining 4/11 cells TBOA enhanced the 1st EPSC and PPF, shown in Figure 4A, but we excluded these cells since interpretation becomes more complex under these circumstances. Note also that TBOA prolonged the recovery of the second of the pair of EPSCs, see Figure 4A, consistent with a slowed recovery of postsynaptic glutamate clearance.Figure 4

Bottom Line: The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse.Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output.Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Brain Health Research Centre, University of Otago School of Medical Sciences, PO Box 56, 9054 Dunedin, New Zealand.

ABSTRACT

Background: Rapid uptake of glutamate by neuronal and glial glutamate transporters (EAATs, a family of excitatory amino acid transporters) is critical for shaping synaptic responses and for preventing excitotoxicity. Two of these transporters, EAAT4 in Purkinje neurons (PN) and EAAT1 in Bergmann glia are both enriched within the cerebellum and altered in a variety of human ataxias.

Results: PN excitatory synaptic responses and firing behaviour following high frequency parallel fibre (PF) activity commonly encountered during sensory stimulation in vivo were adversely influenced by acute inhibition of glutamate transporters. In the presence of a non-transportable blocker of glutamate transporters we observed very large amplitude and duration excitatory postsynaptic currents accompanied by excessive firing of the PNs. A combination of AMPA and mGluR1, but not NMDA, type glutamate receptor activation powered the hyper-excitable PN state. The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse.

Conclusions: Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output. Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

No MeSH data available.


Related in: MedlinePlus