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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 immediate and prolonged burst firing of PNs in response to a short high frequency burst of parallel fibre activity.A, example cell-attached recording from a PN reveals how action potential firing changes during the application of 50 μM TBOA and 50 μM TBOA in the presence of the mGluR antagonist 0.2 mM MCPG. Horizontal bar represents 200 Hz high frequency stimulation to PFs. B, shows a raster plot for the cell shown in A, each sweep (horizontal dots represent each action potential in the sweep) occurred at an interval of 30 seconds during the application of TBOA and TBOA and MCPG (left, vertical bars). Note the enhanced firing after the burst in the presence of TBOA and the inability of MCPG to reduce this. Arrows represent the raster plot for the traces shown above. C, bars show mean values (error bars are sem) of action potential firing frequency obtained from a 500 ms epoch just before stimulation, compared with action potential firing frequency at the peak of the TBOA-induced 200 Hz EPSC (during the 100 ms after the end of the stimulation) and later during the 400 ms after the stimulation when the slower, mGluR1 and EAAT4 dependent phase of the 200 Hz EPSC is active. **** represents P < 0.0001, two way ANOVA, ns is not significant.
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Fig3: Inhibition of glutamate transporters enhances immediate and prolonged burst firing of PNs in response to a short high frequency burst of parallel fibre activity.A, example cell-attached recording from a PN reveals how action potential firing changes during the application of 50 μM TBOA and 50 μM TBOA in the presence of the mGluR antagonist 0.2 mM MCPG. Horizontal bar represents 200 Hz high frequency stimulation to PFs. B, shows a raster plot for the cell shown in A, each sweep (horizontal dots represent each action potential in the sweep) occurred at an interval of 30 seconds during the application of TBOA and TBOA and MCPG (left, vertical bars). Note the enhanced firing after the burst in the presence of TBOA and the inability of MCPG to reduce this. Arrows represent the raster plot for the traces shown above. C, bars show mean values (error bars are sem) of action potential firing frequency obtained from a 500 ms epoch just before stimulation, compared with action potential firing frequency at the peak of the TBOA-induced 200 Hz EPSC (during the 100 ms after the end of the stimulation) and later during the 400 ms after the stimulation when the slower, mGluR1 and EAAT4 dependent phase of the 200 Hz EPSC is active. **** represents P < 0.0001, two way ANOVA, ns is not significant.

Mentions: As shown in Figure 3 TBOA significantly increased the firing frequency at both 0-100 ms and 100-500 ms after the stimulation, compared with basal, pre stimulation firing frequency (Row factor in two way ANOVA F2,24 = 96.8, P < 0.0001). Surprisingly, removal of mGluR1 mediated receptor activation (by MCPG) did not influence the post stimulation firing frequency (not significant in two way ANOVA multiple comparisons). TBOA also did not significantly influence the firing properties of the PN measured in the 500 ms before the PF burst, consistent with the lack of any significant change in holding current of individual PNs by 50 μM TBOA (see Methods).Figure 3


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 immediate and prolonged burst firing of PNs in response to a short high frequency burst of parallel fibre activity.A, example cell-attached recording from a PN reveals how action potential firing changes during the application of 50 μM TBOA and 50 μM TBOA in the presence of the mGluR antagonist 0.2 mM MCPG. Horizontal bar represents 200 Hz high frequency stimulation to PFs. B, shows a raster plot for the cell shown in A, each sweep (horizontal dots represent each action potential in the sweep) occurred at an interval of 30 seconds during the application of TBOA and TBOA and MCPG (left, vertical bars). Note the enhanced firing after the burst in the presence of TBOA and the inability of MCPG to reduce this. Arrows represent the raster plot for the traces shown above. C, bars show mean values (error bars are sem) of action potential firing frequency obtained from a 500 ms epoch just before stimulation, compared with action potential firing frequency at the peak of the TBOA-induced 200 Hz EPSC (during the 100 ms after the end of the stimulation) and later during the 400 ms after the stimulation when the slower, mGluR1 and EAAT4 dependent phase of the 200 Hz EPSC is active. **** represents P < 0.0001, two way ANOVA, ns is not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4549135&req=5

Fig3: Inhibition of glutamate transporters enhances immediate and prolonged burst firing of PNs in response to a short high frequency burst of parallel fibre activity.A, example cell-attached recording from a PN reveals how action potential firing changes during the application of 50 μM TBOA and 50 μM TBOA in the presence of the mGluR antagonist 0.2 mM MCPG. Horizontal bar represents 200 Hz high frequency stimulation to PFs. B, shows a raster plot for the cell shown in A, each sweep (horizontal dots represent each action potential in the sweep) occurred at an interval of 30 seconds during the application of TBOA and TBOA and MCPG (left, vertical bars). Note the enhanced firing after the burst in the presence of TBOA and the inability of MCPG to reduce this. Arrows represent the raster plot for the traces shown above. C, bars show mean values (error bars are sem) of action potential firing frequency obtained from a 500 ms epoch just before stimulation, compared with action potential firing frequency at the peak of the TBOA-induced 200 Hz EPSC (during the 100 ms after the end of the stimulation) and later during the 400 ms after the stimulation when the slower, mGluR1 and EAAT4 dependent phase of the 200 Hz EPSC is active. **** represents P < 0.0001, two way ANOVA, ns is not significant.
Mentions: As shown in Figure 3 TBOA significantly increased the firing frequency at both 0-100 ms and 100-500 ms after the stimulation, compared with basal, pre stimulation firing frequency (Row factor in two way ANOVA F2,24 = 96.8, P < 0.0001). Surprisingly, removal of mGluR1 mediated receptor activation (by MCPG) did not influence the post stimulation firing frequency (not significant in two way ANOVA multiple comparisons). TBOA also did not significantly influence the firing properties of the PN measured in the 500 ms before the PF burst, consistent with the lack of any significant change in holding current of individual PNs by 50 μM TBOA (see Methods).Figure 3

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