Carmen Canavier

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  Mathematical analysis of depolarization block mediated by slow inactivation of the fast sodium channels that limits phasic signaling in midbrain dopamine neurons.
  Carmen Canavier

  Dopamine neurons in freely moving rats often fire behaviorally-relevant high frequency bursts, but depolarization block limits the maximum steady firing rate of dopamine neurons in vitro to approximately 10 Hz. Using a reduced model that faithfully reproduces the sodium current measured in these neurons, we show that adding an additional slow component of sodium channel inactivation, recently observed in these neurons, qualitatively changes in two different ways how the model enters depolarization block. First, the slow time course of inactivation allows multiple spikes with progressively increasing interspike intervals to be elicited during a strong depolarization prior to entry into depolarization block, which may be critical for the ability to burst in vivo. Second, depolarization block occurs much closer to spike threshold, because the additional slow component of inactivation negates the sodium window current. In the absence of the additional slow component of inactivation, this window current produces an S-shaped steady state IV curve that prevents depolarization block in the experimentally observed voltage range near -40 mV. Significantly, the time constant of recovery from slow inactivation during the interspike interval limits the maximum steady firing rate observed prior to entry into depolarization block. These qualitative features of the entry into depolarization block can be reversed experimentally by replacing the native sodium conductance with a virtual one lacking the slow component of inactivation. Our modeling results also suggest that activation of NMDA receptors may contribute to circumventing the firing rate limitation during behaviorally relevant, high frequency bursts in vivo.