Disruption of Dopamine Neuron Activity Pattern Regulation through Selective Expression of a Human KCNN3 Mutation

• Published in: Neuron (Cambridge, Mass.) Mass.), 2013-11, Vol.80 (4), p.997-1009
• Main Authors: Soden, Marta E., Jones, Graham L., Sanford, Christina A., Chung, Amanda S., Güler, Ali D., Chavkin, Charles, Luján, Rafael, Zweifel, Larry S.
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Addictive behaviors; Animals; Attention - physiology; Behavior; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cell culture; Conditioning, Classical - drug effects; Conditioning, Classical - physiology; Dependovirus; Dopamine; Dopamine - metabolism; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Drug dosages; Electrophysiological Phenomena; Excitatory Amino Acid Agonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Hallucinogens - pharmacology; Humans; Immunohistochemistry; In Vitro Techniques; Localization; Mental disorders; Mice; Mice, Transgenic; Motor Activity - drug effects; Motor Activity - physiology; Mutation; N-Methylaspartate - metabolism; Neurons; Parkinson's disease; Physiology; Proteins; Psychomotor Performance - physiology; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - physiology; Reflex, Startle - drug effects; Reflex, Startle - physiology; Rodents; Schizophrenia; Sensory Gating - physiology; Small-Conductance Calcium-Activated Potassium Channels - genetics; Substance abuse treatment
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.07.044

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. •SK channels regulate dopamine neuron activity patterns•Altered dopamine activity patterns disrupt attention and sensory gating•Suppression of SK channels potentiates NMDA-mediated synaptic transmission Soden et al. demonstrate that expression of a dominant-negative mutation in the human KCNN3 gene, which encodes the calcium-activated potassium channel SK3, in dopamine neurons of mice alters activity patterns of these neurons, disrupting attention and sensory gating processes.