期刊
NEURON
卷 80, 期 4, 页码 997-1009出版社
CELL PRESS
DOI: 10.1016/j.neuron.2013.07.044
关键词
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资金
- National Science Foundation [DGE0718124]
- Life Sciences Research Fellowships
- Howard Hughes Medical Institute
- Spanish Ministry of Education and Science [BFU-2012-38348, CSD2008-00005]
- National Institutes of Health [5T32DA727817, KO5DA020570, P30MH089887, 1R01MH094536]
The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3 Delta) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3 Delta suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3 Delta increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3 Delta led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.
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