Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons.
The physiological activity of dopaminergic midbrain (DA) neurons is important for movement, cognition, and reward. Altered activity of DA neurons is a key finding in schizophrenia, but the cellular mechanisms have not been identified. Recently, KCNN3, a gene that encodes a member (SK3) of the small-conductance, calcium-activated potassium (SK) channels, has been proposed as a candidate gene for schizophrenia. However, the functional role of SK3 channels in DA neurons is unclear. We combined patch-clamp recordings with single-cell RT-PCR and confocal immunohistochemistry in mouse midbrain slices to study the function of molecularly defined SK channels in DA neurons. Biophysical and pharmacological analysis, single-cell mRNA, and protein expression profiling strongly suggest that SK3 channels mediate the calcium-dependent afterhyperpolarization in DA neurons. Perforated patch recordings of DA neurons in the substantia nigra (SN) demonstrated that SK3 channels dynamically control the frequency of spontaneous firing. In addition, SK3 channel activity was essential to maintain the high precision of the intrinsic pacemaker of DA SN neurons. In contrast, in the ventral tegmental area, DA neurons displayed significantly smaller SK currents and lower SK3 protein expression. In these DA neurons, SK3 channels were not involved in pacemaker control. Accordingly, they discharged in a more irregular manner compared with DA SN neurons. Thus, our study shows that differential SK3 channel expression is a critical molecular mechanism in DA neurons to control neuronal activity. This provides a cellular framework to understand the functional consequences of altered SK3 expression, a candidate disease mechanism for schizophrenia.
Wolfart
J
J
Medical Research Council, Anatomical Neuropharmacology Unit, Department of Pharmacology, Oxford University, Oxford OX1 3TH, United Kingdom.
Neuhoff
H
H
Franz
O
O
Roeper
J
J
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001683:Biological Clocks / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D024681:Potassium Channels, Calcium-Activated; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; C406328:KCNN3 protein, human; C496900:Kcnn3 protein, mouse; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; C102635:1-ethyl-2-benzimidazolinone; D004298:Dopamine