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A selective interplay between aberrant EPSPKA and INaP reduces spike timing precision in dentate granule cells of epileptic rats.

Epsztein J, Sola E, Represa A, Ben-Ari Y, Crépel V - Cereb. Cortex (2009)

Bottom Line: We report that, in contrast to time-locked spikes generated by EPSP(AMPA) in control DGCs, aberrant EPSP(KA) are associated with long-lasting plateaus and jittered spikes during single-spike mode firing.Importantly, EPSP(KA) not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through I(NaP) activation.We conclude that a selective interplay between aberrant EPSP(KA) and I(NaP) severely alters the temporal precision of EPSP-spike coupling in DGCs of chronic epileptic rats.

View Article: PubMed Central - PubMed

Affiliation: INMED, INSERM U901, Université de La Méditerranée, Parc scientifique de Luminy, BP 13, 13273, Marseille Cedex 09, France.

ABSTRACT
Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input-output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor-mediated excitatory postsynaptic potentials (EPSP(KA)) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSP(AMPA) in control DGCs, aberrant EPSP(KA) are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSP(KA) through persistent sodium current (I(NaP)) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSP(KA) activates I(NaP) and generates jittered spikes. Conversely in epileptic rats, blockade of EPSP(KA) or I(NaP) restores the temporal precision of EPSP-spike coupling. Importantly, EPSP(KA) not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through I(NaP) activation. We conclude that a selective interplay between aberrant EPSP(KA) and I(NaP) severely alters the temporal precision of EPSP-spike coupling in DGCs of chronic epileptic rats.

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Decreased temporal precision of EPSP–spike coupling in epileptic rats. (A) In a granule cell from a control rat, spikes were generated on the rising phase of the EPSPs (stimulation at arrow) at short latencies and with little variability (black traces on the left, mean latency SD = 0.9 ms, Vm = −51.4 mV). In a granule cell from an epileptic rat, spikes occurred both at short and at long latencies with a large variability (red traces on the right, mean latency SD = 12.6 ms, Vm = −51.3 mV). Traces are aligned at EPSP onset. (B) Spike latency histograms of the cells shown in A (control: black columns, n = 75 spikes; epileptic: red columns, n = 77 spikes). (C) Bar graph of the mean EPSP–spike latency SD in control cells (n = 38) and in cells from epileptic rats (n = 23, **P < 0.01). (D) Superimposed subthreshold EPSPs recorded simultaneously to the suprathreshold EPSPs shown in A in the same cells from control (grey traces, left) and epileptic (pink traces, right) rats at threshold holding potential; black and red traces depict the average subthreshold EPSPs from control (left) and epileptic (right) rats, respectively. (E) Scatter plots of the EPSP–spike (E–S) latency and latency SD plotted against EPSP half width (hw) for n = 38 granule cells from control (black circles) and n = 23 granule cells from epileptic rats (red circles). Note that in this and following figures, spikes are truncated and electrical stimulations (performed in the inner one-third of the molecular layer of the dentate gyrus) are indicated by black arrows below the traces; all recordings were performed in the presence of 10 μM bicuculline, 40 μM D-APV (or 10 μM MK801), and 5 μM CGP 55845, except when otherwise stated.
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fig1: Decreased temporal precision of EPSP–spike coupling in epileptic rats. (A) In a granule cell from a control rat, spikes were generated on the rising phase of the EPSPs (stimulation at arrow) at short latencies and with little variability (black traces on the left, mean latency SD = 0.9 ms, Vm = −51.4 mV). In a granule cell from an epileptic rat, spikes occurred both at short and at long latencies with a large variability (red traces on the right, mean latency SD = 12.6 ms, Vm = −51.3 mV). Traces are aligned at EPSP onset. (B) Spike latency histograms of the cells shown in A (control: black columns, n = 75 spikes; epileptic: red columns, n = 77 spikes). (C) Bar graph of the mean EPSP–spike latency SD in control cells (n = 38) and in cells from epileptic rats (n = 23, **P < 0.01). (D) Superimposed subthreshold EPSPs recorded simultaneously to the suprathreshold EPSPs shown in A in the same cells from control (grey traces, left) and epileptic (pink traces, right) rats at threshold holding potential; black and red traces depict the average subthreshold EPSPs from control (left) and epileptic (right) rats, respectively. (E) Scatter plots of the EPSP–spike (E–S) latency and latency SD plotted against EPSP half width (hw) for n = 38 granule cells from control (black circles) and n = 23 granule cells from epileptic rats (red circles). Note that in this and following figures, spikes are truncated and electrical stimulations (performed in the inner one-third of the molecular layer of the dentate gyrus) are indicated by black arrows below the traces; all recordings were performed in the presence of 10 μM bicuculline, 40 μM D-APV (or 10 μM MK801), and 5 μM CGP 55845, except when otherwise stated.

Mentions: The kinetics of synaptic events was analyzed using MiniAnalysis 6.0.1 (Synaptosoft, Decatur, GA). The experiments performed in the presence of AMPAR antagonist [50–100 μM 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466)] or KAR blocker [10 μM (2S,4R)-4-methylglutamic acid (SYM 2081)] enabled us to determine the statistical limit to classify events as EPSPKA (half width > 50 ms, see Fig. 2) or EPSPAMPA (half width < 50 ms, P < 0.05, see Figs 1 and 2), respectively. The charge transfer through the AMPAR- and KAR-mediated EPSP was calculated as the EPSP integral on 400-ms time window from onset. MiniAnalysis 6.0.1 was also used for the measurement of amplitude of action potentials (from threshold defined as the membrane potential at which the rate-of-rise of voltage crossed 50 V/s; Kole and Stuart 2008) and half width of action potentials. Calculation of firing probability was based on the calculation of the ratio of suprathreshold EPSPs over all EPSPs using 100 trials of electrical stimulation.


A selective interplay between aberrant EPSPKA and INaP reduces spike timing precision in dentate granule cells of epileptic rats.

Epsztein J, Sola E, Represa A, Ben-Ari Y, Crépel V - Cereb. Cortex (2009)

Decreased temporal precision of EPSP–spike coupling in epileptic rats. (A) In a granule cell from a control rat, spikes were generated on the rising phase of the EPSPs (stimulation at arrow) at short latencies and with little variability (black traces on the left, mean latency SD = 0.9 ms, Vm = −51.4 mV). In a granule cell from an epileptic rat, spikes occurred both at short and at long latencies with a large variability (red traces on the right, mean latency SD = 12.6 ms, Vm = −51.3 mV). Traces are aligned at EPSP onset. (B) Spike latency histograms of the cells shown in A (control: black columns, n = 75 spikes; epileptic: red columns, n = 77 spikes). (C) Bar graph of the mean EPSP–spike latency SD in control cells (n = 38) and in cells from epileptic rats (n = 23, **P < 0.01). (D) Superimposed subthreshold EPSPs recorded simultaneously to the suprathreshold EPSPs shown in A in the same cells from control (grey traces, left) and epileptic (pink traces, right) rats at threshold holding potential; black and red traces depict the average subthreshold EPSPs from control (left) and epileptic (right) rats, respectively. (E) Scatter plots of the EPSP–spike (E–S) latency and latency SD plotted against EPSP half width (hw) for n = 38 granule cells from control (black circles) and n = 23 granule cells from epileptic rats (red circles). Note that in this and following figures, spikes are truncated and electrical stimulations (performed in the inner one-third of the molecular layer of the dentate gyrus) are indicated by black arrows below the traces; all recordings were performed in the presence of 10 μM bicuculline, 40 μM D-APV (or 10 μM MK801), and 5 μM CGP 55845, except when otherwise stated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837093&req=5

fig1: Decreased temporal precision of EPSP–spike coupling in epileptic rats. (A) In a granule cell from a control rat, spikes were generated on the rising phase of the EPSPs (stimulation at arrow) at short latencies and with little variability (black traces on the left, mean latency SD = 0.9 ms, Vm = −51.4 mV). In a granule cell from an epileptic rat, spikes occurred both at short and at long latencies with a large variability (red traces on the right, mean latency SD = 12.6 ms, Vm = −51.3 mV). Traces are aligned at EPSP onset. (B) Spike latency histograms of the cells shown in A (control: black columns, n = 75 spikes; epileptic: red columns, n = 77 spikes). (C) Bar graph of the mean EPSP–spike latency SD in control cells (n = 38) and in cells from epileptic rats (n = 23, **P < 0.01). (D) Superimposed subthreshold EPSPs recorded simultaneously to the suprathreshold EPSPs shown in A in the same cells from control (grey traces, left) and epileptic (pink traces, right) rats at threshold holding potential; black and red traces depict the average subthreshold EPSPs from control (left) and epileptic (right) rats, respectively. (E) Scatter plots of the EPSP–spike (E–S) latency and latency SD plotted against EPSP half width (hw) for n = 38 granule cells from control (black circles) and n = 23 granule cells from epileptic rats (red circles). Note that in this and following figures, spikes are truncated and electrical stimulations (performed in the inner one-third of the molecular layer of the dentate gyrus) are indicated by black arrows below the traces; all recordings were performed in the presence of 10 μM bicuculline, 40 μM D-APV (or 10 μM MK801), and 5 μM CGP 55845, except when otherwise stated.
Mentions: The kinetics of synaptic events was analyzed using MiniAnalysis 6.0.1 (Synaptosoft, Decatur, GA). The experiments performed in the presence of AMPAR antagonist [50–100 μM 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466)] or KAR blocker [10 μM (2S,4R)-4-methylglutamic acid (SYM 2081)] enabled us to determine the statistical limit to classify events as EPSPKA (half width > 50 ms, see Fig. 2) or EPSPAMPA (half width < 50 ms, P < 0.05, see Figs 1 and 2), respectively. The charge transfer through the AMPAR- and KAR-mediated EPSP was calculated as the EPSP integral on 400-ms time window from onset. MiniAnalysis 6.0.1 was also used for the measurement of amplitude of action potentials (from threshold defined as the membrane potential at which the rate-of-rise of voltage crossed 50 V/s; Kole and Stuart 2008) and half width of action potentials. Calculation of firing probability was based on the calculation of the ratio of suprathreshold EPSPs over all EPSPs using 100 trials of electrical stimulation.

Bottom Line: We report that, in contrast to time-locked spikes generated by EPSP(AMPA) in control DGCs, aberrant EPSP(KA) are associated with long-lasting plateaus and jittered spikes during single-spike mode firing.Importantly, EPSP(KA) not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through I(NaP) activation.We conclude that a selective interplay between aberrant EPSP(KA) and I(NaP) severely alters the temporal precision of EPSP-spike coupling in DGCs of chronic epileptic rats.

View Article: PubMed Central - PubMed

Affiliation: INMED, INSERM U901, Université de La Méditerranée, Parc scientifique de Luminy, BP 13, 13273, Marseille Cedex 09, France.

ABSTRACT
Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input-output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor-mediated excitatory postsynaptic potentials (EPSP(KA)) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSP(AMPA) in control DGCs, aberrant EPSP(KA) are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSP(KA) through persistent sodium current (I(NaP)) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSP(KA) activates I(NaP) and generates jittered spikes. Conversely in epileptic rats, blockade of EPSP(KA) or I(NaP) restores the temporal precision of EPSP-spike coupling. Importantly, EPSP(KA) not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through I(NaP) activation. We conclude that a selective interplay between aberrant EPSP(KA) and I(NaP) severely alters the temporal precision of EPSP-spike coupling in DGCs of chronic epileptic rats.

Show MeSH
Related in: MedlinePlus