Contribution of a slowly inactivating potassium current to the transition to firing of neostriatal spiny projection neurons

E. S. Nisenbaum, Z. C. Xu, C. J. Wilson

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Abstract

1. Neostriatal spiny projection neurons display a prominent slowly depolarizing (ramp) potential and long latency to spike discharge in response to intracellular current pulses. The contribution of a slowly inactivating A- current (I(As)) to this delayed excitation was investigated in a neostriatal slice preparation using current pulse protocols incorporating information based on the known voltage dependence, kinetics, and pharmacological properties of I(As). 2. Depolarizing intracellular current pulses evoked a slowly developing ramp potential that could last for seconds without reaching steady state and continued until either the pulse was terminated or spike threshold was reached. The slope of the ramp potential was dependent on the level of depolarization achieved by the membrane, and the apparent activation threshold for this ramp depolarization was approximately -65 mV. 3. Application of low concentrations of 4-aminopyridine (4-AP, 30-100 μM) or dendrotoxin (DTX, 30 nM), which are known to selectively block I(As), reduced both the slope of the ramp potential and the latency to first spike discharge. As has been described previously, blockade of inward Na+ and Ca2+ currents with tetrodotoxin (TTX, 1 μM) and cadmium (400 μM) also reduced the slope of the ramp depolarization. 4. A conditioning-test pulse protocol was used to examine the voltage dependence of inactivation of the ramp potential and long first spike latency. In the absence of a conditioning pulse, the test pulse evoked a slowly rising ramp potential and a spike with a long latency to discharge. A conditioning depolarization to approximately - 60 mV decreased the slope of the ramp potential and the latency to first spike discharge evoked by the test pulse. A conditioning hyperpolarization to potentials below -100 mV, increased first spike latency. Application of a low concentration of 4-AP (100 μM) abolished the influence of prior membrane potential on the slope of the ramp depolarization and the latency to first spike discharge. 5. The kinetics of recovery from inactivation of the 4-AP- sensitive current were studied in the presence of TTX and cadmium by depolarizing cells to approximately -50 mV and then stepping to approximately -90 mV for increasing periods of time (0.5-5.0 s) before delivering a test pulse. The amplitude of the test pulse response decreased as a function of the hyperpolarizing step duration. When the test pulse response amplitudes were plotted against the hyperpolarizing step duration, the points reflected an exponential decay with an average time constant of 2.05 ± 1.38 (SD) s. Application of 4-AP (100 μM) blocked the effect of hyperpolarizing step duration on the test pulse response amplitude such that all responses were of equal amplitude. 6. Administration of 4-AP (100 μM) depolarized spiny neurons by 7.4 ± 6.1 mV and revealed spontaneous synaptic potentials. The input resistance of spiny cells was not increased by 4-AP alone, presumably because of the increased conductance produced by the tonic spontaneous synaptic input. However, after blocking this synaptic input with TTX (1 μM) and cadmium (400 μM), 4-AP (100 μM) increased the input resistance of these cells and revealed a pronounced outward rectification at potentials above - 50 mV. A portion of this rectification was eliminated by a higher concentration of 4-AP (2 mM), which is known to block a fast-inactivating A- current in spiny cells. 7. On the basis of similarities between the delayed excitation and I(As) in terms of their voltage dependence of activation and inactivation, kinetics of inactivation and recovery from inactivation, and sensitivity to 4-AP and DTX, we conclude that I(As) contributes to the ramp potential and long latency to spike discharge in striatal spiny neurons. The data also suggest that I(As) competes with inward Na+ and Ca2+ currents acting to slow the rate of depolarization, giving rise to the ramp potential and delayed spike discharge. 8. Neostriatal spiny neurons recorded in intact animals are known to exhibit shifts in their membrane potentials from hyperpolarized to depolarized states in response to synchronous excitatory synaptic input from cortex and/or thalamus. The voltage dependence and kinetics of I(As) indicate that the availability of this current to influence the depolarizing shifts will depend dramatically on the recent voltage history of the cell. Thus, if the cell has been in the hyperpolarized state for a long period before receiving the synaptic barrage, then much of the inactivation of I(As) will have been removed, reducing the level of the response. In contrast, if the cell has been in the hyperpolarized state for a brief period of time, then I(As) will be mostly inactivated, permitting a larger response to the synaptic input.

Original languageEnglish (US)
Pages (from-to)1174-1189
Number of pages16
JournalJournal of Neurophysiology
Volume71
Issue number3
DOIs
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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