The substantia nigra dopaminergic (SNDA) neurons are among the best studied in the CNS for their implication in the Parkinson’s disease. They present a complement of voltage-dependent currents, among which a typical I(h). SNDA neurons are autorhythmic, and it is therefore not surprising that numerous papers have investigated the role of I(h) in the spontaneous activity. However, the block of this current does not entail any significant alteration of the firing frequency, so that role of I(h) is still not well understood. We have re-examined this problem studying the h-current in thin slices in conditions that were different from most of the previous studies under two key aspects: we worked at 37°C and, in most of the experiments, in perforated patch. The first step has been a complete kinetic characterization of the current, leading to a satisfactory HH model of this conductance in physiological conditions. The experimental conditions adopted evidenced that the contribution of the h-current to the excitability profile of these cells has been probably underestimated under several aspects. First, it should be considered the effect of temperature, with its consequences in the kinetic properties of the I(h). The Q10 that we measured for I(h) amplitude in condition of open channel was 3.35, similar to the value described in other preparations. However, the Q10 for the time constant of activation (measured as the ratio of the reciprocals of time constants at -100 mV) was a surprising 10.8, meaning that the current at 37 °C activates much faster that previously estimated at room temperature. Furthermore, the temperature affected significantly also the midpoint of activation, promoting a shift from -95 to -84 mV, implying activation at potentials much more positive than previously reported, and a significant degree of opening already at potentials of physiological interest. A relevant functional implication is that, due to the relatively high time constant of deactivation (> 0.6 s), there is an important activity-dependent memory effect evoked by trains of inhibitory synaptic inputs already at -70 mV. Second, it should be taken into account that the variation of the cytoplasmic concentration of cyclic nucleotides has large effects on the I(h) amplitude, an effect that can be seen only in perforated patches: forskolin at 37 °C increases the I(h) amplitude of +51.6% at -100 mV, due to a shift of the midpoint of activation (+4.8 mV), and promotes a 31% decrease of the time constant of activation. This modulatory mechanism of I(h) mediated by cAMP might have important functional consequences for the numerous second-messenger mediated signaling systems present in SNDA neurons.

Properties of hyperpolarization-activated cationic I(h) current in the rat substantia nigra pars compacta neurons

BELLUZZI, Ottorino;GAMBARDELLA, Cristina;PIGNATELLI, Angela
2010

Abstract

The substantia nigra dopaminergic (SNDA) neurons are among the best studied in the CNS for their implication in the Parkinson’s disease. They present a complement of voltage-dependent currents, among which a typical I(h). SNDA neurons are autorhythmic, and it is therefore not surprising that numerous papers have investigated the role of I(h) in the spontaneous activity. However, the block of this current does not entail any significant alteration of the firing frequency, so that role of I(h) is still not well understood. We have re-examined this problem studying the h-current in thin slices in conditions that were different from most of the previous studies under two key aspects: we worked at 37°C and, in most of the experiments, in perforated patch. The first step has been a complete kinetic characterization of the current, leading to a satisfactory HH model of this conductance in physiological conditions. The experimental conditions adopted evidenced that the contribution of the h-current to the excitability profile of these cells has been probably underestimated under several aspects. First, it should be considered the effect of temperature, with its consequences in the kinetic properties of the I(h). The Q10 that we measured for I(h) amplitude in condition of open channel was 3.35, similar to the value described in other preparations. However, the Q10 for the time constant of activation (measured as the ratio of the reciprocals of time constants at -100 mV) was a surprising 10.8, meaning that the current at 37 °C activates much faster that previously estimated at room temperature. Furthermore, the temperature affected significantly also the midpoint of activation, promoting a shift from -95 to -84 mV, implying activation at potentials much more positive than previously reported, and a significant degree of opening already at potentials of physiological interest. A relevant functional implication is that, due to the relatively high time constant of deactivation (> 0.6 s), there is an important activity-dependent memory effect evoked by trains of inhibitory synaptic inputs already at -70 mV. Second, it should be taken into account that the variation of the cytoplasmic concentration of cyclic nucleotides has large effects on the I(h) amplitude, an effect that can be seen only in perforated patches: forskolin at 37 °C increases the I(h) amplitude of +51.6% at -100 mV, due to a shift of the midpoint of activation (+4.8 mV), and promotes a 31% decrease of the time constant of activation. This modulatory mechanism of I(h) mediated by cAMP might have important functional consequences for the numerous second-messenger mediated signaling systems present in SNDA neurons.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/1687132
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