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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 (hSK3?) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3? 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? increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3? 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.

SUBMITTER: Soden ME

PROVIDER: S-EPMC3840077 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

Soden Marta E ME Jones Graham L GL Sanford Christina A CA Chung Amanda S AS Güler Ali D AD Chavkin Charles C Luján Rafael R Zweifel Larry S LS

Neuron 20131024 4

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. Consi ...[more]

PMID: 24206670

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Project description:Strategy switching is a form of cognitive flexibility that requires inhibiting a previously successful strategy and switching to a new strategy of a different categorical modality. It is dependent on dopamine (DA) receptor activation and release in ventral striatum and prefrontal cortex, two primary targets of ventral tegmental area (VTA) DA projections. Although the circuitry that underlies strategy switching early in learning has been studied, few studies have examined it after extended discrimination training. This may be important as DA activity and release patterns change across learning, with several studies demonstrating a critical role for substantia nigra pars compacta (SNc) DA activity and release once behaviors are well-learned. We have demonstrated that medial septum (MS) activation simultaneously increased VTA and decreased SNc DA population activity, as well as improved reversal learning via these actions on DA activity. We hypothesized that MS activation would improve strategy switching both early in learning and after extended training through its ability to increase VTA DA population activity and decrease SNc DA population activity, respectively. We chemogenetically activated the MS of male and female rats and measured their performance on an operant-based strategy switching task following 1, 10, or 15 days of discrimination training. Contrary to our hypothesis, MS activation did not affect strategy switching after 1 day of discrimination training. MS activation improved strategy switching after 10 days of training, but only in females. MS activation improved strategy switching in both sexes after 15 days of training. Infusion of bicuculline into the ventral subiculum (vSub) inhibited the MS-mediated decrease in SNc DA population activity and attenuated the improvement in strategy switching. Intra-vSub infusion of scopolamine inhibited the MS-mediated increase in VTA DA population activity but did not affect the improvement in strategy switching. Intra-vSub infusion of both bicuculline and scopolamine inhibited the MS-mediated effects on DA population activity in both the SNc and VTA and completely prevented the improvement in strategy switching. These data indicate that MS activation improves strategy switching once the original strategy has been sufficiently well-learned, and that this may occur via the MS's regulation of DA neuron responsivity.

Dataset Information

Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

Publications

Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

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