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. 2006 Feb 15;26(7):1906-12.
doi: 10.1523/JNEUROSCI.4430-05.2006.

Alcohol potently modulates climbing fiber-->Purkinje neuron synapses: role of metabotropic glutamate receptors

Mario Carta  1 , Manuel Mameli, C Fernando Valenzuela
Affiliations

Alcohol potently modulates climbing fiber-->Purkinje neuron synapses: role of metabotropic glutamate receptors

Mario Carta et al. J Neurosci. .

Abstract

Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca2+ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber-->Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mm (legal blood alcohol level in the United States is below 0.08 g/dl = 17 mm).

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Figures

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EtOH modulates the late phase of the CS. A1, B1, Sample traces illustrating the effect of 50 mm EtOH on the late phase of the CS. The corresponding cumulative CS integrals are shown in the insets. A2, B2, The same traces are shown at a more compressed time scale to further illustrate the effect of EtOH. Note that the timing but not the amplitude of the afterhyperpolarization is altered. Ctrl, Control. C, Time course of the effect of 50 mm EtOH (n = 16–18 neurons). D, Summary of the effect of increasing concentrations of EtOH. n = 6 (10 mm), 6 (25 mm), 18 (50 mm), 7 (75 mm). *p < 0.05; ***p < 0.001 by one-sample t test versus a theoretical mean of 100. Error bars represent SEM. See Results for one-way ANOVA.
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EtOH does not affect Purkinje cell Ca2+ transients elicited by CF stimulation. A, Image of a PN filled with 100–150 μm fura-2 AM via the patch electrode illustrating the areas used for analysis. B1–B4, Averaged Ca2+ transients elicited in the soma, a proximal dendrite, and two distal dendrites in the absence and presence of EtOH (n = 6 neurons). The averages of transients obtained 1–4 min [control (ctrl)] and 6–9 min (EtOH) after initiation of recording are shown. Electrophysiological recordings were simultaneously obtained from these six neurons, and these revealed an effect of EtOH on CS area in all cases (data shown as part of Fig. 1C). C, Lack of an effect of EtOH on Ca2+ transient amplitude in a distal dendrite. Error bars represent SEM.
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Blockade of mGluR1 mimics and occludes the effect of EtOH on CS area. A, Effect of the mGluR1 antagonist LY367385 (50 μm) in the absence and presence of 50 mm EtOH. Ctrl, Control. B, Time course graph corresponding to the same recording shown in A. C, Effects of LY367385 on CS area and amplitude of the fast Na+ spike in the absence and presence of 50 mm EtOH (n = 4–6; ***p < 0.001 by one-sample t test vs a theoretical mean of 100). Error bars represent SEM.
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EtOH inhibits mGluR1-dependent EPSCs evoked by CF stimulation in PNs. A, Stimulation of CFs with a train of four pulses at a frequency of 20 Hz in the presence of 10 μm NBQX and 20 μm bicuculline elicited EPSCs that were inhibited by EtOH (50 mm). These EPSCs were abolished by the mGluR1 antagonist LY367385 (50 μm). B, Time course of the effect of EtOH and LY367385 for the same cell shown in A. C, Sample traces of recordings obtained as described in A but in the presence of the glutamate transporter inhibitor TBOA (100 μm). D, Effect of 50 mm EtOH on the amplitude of mGluR1-dependent EPSCs in the absence (n = 5) and presence (n = 4) of TBOA. The effect of 50 μm LY367385 is also shown. Because the effect of LY367385 was the same in the absence and presence of TBOA, the data were combined (n = 9). **p < 0.01 versus EtOH and EtOH plus TBOA by one-way ANOVA followed by Tukey’s post hoc test. A one-sample t test revealed that all sets of data were significantly different from 100% (p < 0.006; data not shown). ctrl, Control. Error bars represent SEM.
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EtOH does not affect the PPR of AMPAR-mediated EPSCs evoked by CF stimulation. A, CF stimulation with pairs of stimuli at an interpulse interval of 50 ms elicited EPSCs that exhibited paired-pulse depression. These events were inhibited by NBQX (10 μm; data not shown). EtOH did not affect either the PPR or the amplitude of the first EPSC. B, Lack of an effect of EtOH on these parameters (n = 8). Events were normalized with respect to the initial PPR or amplitude (i.e., first 3 min of recording). C, Lowering the extracellular Ca2+ concentration to 0.5 mm decreased paired-pulse depression. EtOH did not affect either the PPR or the amplitude of the first EPSC, even under these conditions of low glutamate release probability. D, Effect of lowering extracellular Ca2+ levels on the PPR (n = 7). E, Lack of an effect of EtOH on the PPR under low Ca2+ conditions (n = 7). The error bar for the control group is not visible. F, Effect of lowering extracellular Ca2+ levels on the amplitude of the first EPSC (n = 7) and lack of an effect of EtOH on EPSC amplitude under low Ca2+ conditions (n = 7). Ctrl, Control; Reg, regular; W/O, washout. Error bars represent SEM.
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EtOH inhibits CF LTD. A, AMPAR-mediated EPSCs evoked by CF stimulation during baseline (solid line) and 20 min after tetanization (Post 20′; dotted line; 5 Hz for 30 s). Note that tetanization induced LTD of the amplitude of these events under control conditions (left). Traces from a different PN illustrating that LTD could not be induced in presence of 50 mm EtOH are shown on the right. B, CF EPSC amplitude changes (percentage) in control and EtOH-exposed neurons (n = 6). The duration of the EtOH exposure is represented by the bar. The time of tetanization is represented by the arrow. Error bars represent SEM.
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