Dataset Information

Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

ABSTRACT:

Background

The calmodulin/calcium-activated K(+) channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice.

Methodology/principal findings

In the open field test, KCa3.1-deficiency increased horizontal activity, as KCa3.1(-/-) mice travelled longer distances (?145% of KCa3.1(+/+)) and at higher speed (?1.5-fold of KCa3.1(+/+)). Working memory in the Y-maze was reduced by KCa3.1-deficiency. Motor coordination on the rotarod and neuromuscular functions were unchanged. In KCa3.1(-/-) mice, HPLC analysis revealed that turn-over rates of serotonin were reduced in frontal cortex, striatum and brain stem, while noradrenalin turn-over rates were increased in the frontal cortex. Dopamine turn-over rates were unaltered. Plasma catecholamine and corticosterone levels were unaltered. Intraperitoneal injections of 10 mg/kg of the KCa3.1/KCa2-activator SKA-31 reduced rearing and turning behavior in KCa3.1(+/+) but not in KCa3.1(-/-) mice, while 30 mg/kg SKA-31 caused strong sedation in 50% of the animals of either genotypes. KCa3.1(-/-) mice were hyperactive (?+60%) in their home cage and SKA-31-administration reduced nocturnal physical activity in KCa3.1(+/+) but not in KCa3.1(-/-) mice.

Conclusions/significance

KCa3.1-deficiency causes locomotor hyperactivity and altered monoamine levels in selected brain regions, suggesting a so far unknown functional link of KCa3.1 channels to behavior and monoaminergic neurotransmission in mice. The tranquilizing effects of low-dose SKA-31 raise the possibility to use KCa3.1/KCa2 channels as novel pharmacological targets for the treatment of neuropsychiatric hyperactivity disorders.

SUBMITTER: Lambertsen KL

PROVIDER: S-EPMC3471871 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

Lambertsen Kate Lykke KL Gramsbergen Jan Bert JB Sivasaravanaparan Mithula M Ditzel Nicholas N Sevelsted-Møller Linda Maria LM Oliván-Viguera Aida A Rabjerg Maj M Wulff Heike H Köhler Ralf R

PloS one 20121015 10

<h4>Background</h4>The calmodulin/calcium-activated K(+) channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice.<h4>Methodology/principal findings</h4>In the open field test, KCa3.1-d ...[more]

PMID: 23077667

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Project description:RationaleAmylin receptors consist of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs). The identification of amylin receptors in areas processing reward, namely laterodorsal tegmental area (LDTg), ventral tegmental area (VTA), and nucleus accumbens (NAc), has attributed them a role as reward regulators. Indeed, acute activation of amylin receptors by the amylin receptor agonist salmon calcitonin (sCT) attenuates alcohol-induced behaviours in rodents.ObjectivesThe effects of long-term administration of sCT on alcohol-related behaviours and the molecular mechanisms underlying these processes are not yet elucidated. To fill this knowledge gap, we investigated the effects of sub-chronic sCT treatment on the locomotor stimulatory responses to alcohol in mice and the molecular pathways involved.MethodsWe assessed the behavioural effects of sub-chronic sCT treatment by means of locomotor activity experiments in mice. We used western blot to identify changes of the CTR levels and ex vivo biochemical analysis to detect changes in monoamines and their metabolites.ResultsAfter discontinuation for 5 days of sCT treatment, alcohol did not induce locomotor stimulation in mice pre-treated with sCT when compared with vehicle, without altering secondary behavioural parameters of the locomotor activity experiment or the protein levels of the CTR in reward-related areas in the same set of animals. Moreover, repeated sCT treatment altered monoaminergic neurotransmission in various brain areas, including increased serotonin and decreased dopamine turnover in the VTA. Lastly, we identified a differential effect of repeated sCT and acute alcohol administration on alcohol-induced locomotion in mice, where sCT initially attenuated and later increased this alcohol response. It was further found that this treatment combination did not affect secondary behavioural parameters measured in this locomotor activity experiments.ConclusionsThese data suggest that sub-chronic sCT treatment differentially alters the ability of alcohol to cause locomotor stimulation, possibly through molecular mechanisms involving various neurotransmitter systems and not the CTR levels per se.

Dataset Information

Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

Background

Methodology/principal findings

Conclusions/significance

Publications

Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

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