title: Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.
abstract: 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 (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ 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, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ 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.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Soden
authors.forename: Graham L
authors.initials: GL
authors.lastname: Jones
authors.forename: Christina A
authors.initials: CA
authors.lastname: Sanford
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Chung
authors.forename: Ali D
authors.initials: AD
authors.lastname: Güler
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Larry S
authors.initials: LS
authors.lastname: Zweifel
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001288:Attention / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D000229:Dependovirus; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D055724:Electrophysiological Phenomena; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006213:Hallucinogens / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*
chemical_list: D018690:Excitatory Amino Acid Agonists; D006213:Hallucinogens; C406328:KCNN3 protein, human; D016194:Receptors, N-Methyl-D-Aspartate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D016202:N-Methylaspartate; D004298:Dopamine