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The Journal of Neuroscience, December 8, 2004, 24(49):11079-11087; doi:10.1523/JNEUROSCI.2713-04.2004

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Cellular/Molecular
Spontaneous Opening of T-Type Ca²⁺ Channels Contributes to the Irregular Firing of Dopamine Neurons in Neonatal Rats

Guohong Cui, Takashi Okamoto, and Hitoshi Morikawa

Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology and Institute for Neuroscience, University of Texas, Austin, Texas 78712

During early postnatal development, midbrain dopamine (DA) neurons display anomalous firing patterns and amphetamine response. Spontaneous miniature hyperpolarizations (SMHs) are observed in DA neurons during the same period but not in adults. These hyperpolarizations have been shown to be dependent on the release of Ca²⁺ from internal stores and the subsequent activation of Ca²⁺-sensitive K⁺ channels. However, the triggering mechanism and the functional significance of SMHs remain poorly understood. To address these issues, using brain slices, we recorded spontaneous miniature outward currents (SMOCs) in DA neurons of neonatal rats. Two types of SMOCs were identified based on the peak amplitude. Both types were suppressed by intracellular dialysis of ruthenium red, a ryanodine receptor (RyR) antagonist, yet none of the known Ca²⁺-releasing messengers were involved. T-type Ca²⁺ channel blockers (Ni²⁺ and mibefradil) inhibited large-amplitude SMOCs without affecting the small-amplitude ones. The voltage dependence of SMOCs displayed a peak of approximately -50 mV, consistent with the involvement of low-threshold T-type Ca²⁺ channels. Blockade of SMOCs with cyclopiazonic acid or ryanodine converted the irregular firing of DA neurons in neonatal rats into an adult-like pacemaker pattern. This effect was reversed by the injection of artificial currents mimicking SMOCs. Finally, amphetamine inhibited SMOCs and transformed the irregular firing pattern into a more regular one. These data demonstrate that Ca²⁺ influx through T-type Ca²⁺ channels, followed by Ca²⁺-induced Ca²⁺ release via RyRs, contributes to the generation of SMOCs. We propose that SMOCs-SMHs may underlie the anomalous firing and amphetamine response of DA neurons during the postnatal developmental period.

Key words: intracellular Ca²⁺ signaling; T-type Ca²⁺ channels; SK channels; ryanodine receptors; dopamine neurons; firing pattern

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Received July 7, 2004; revised October 1, 2004; accepted October 20, 2004.

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