Genetic KCa3.1-Deficiency Produces Locomotor Hyperactivity and Alterations in Cerebral Monoamine Levels

Abstract

BackgroundThe 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 FindingsIn 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/SignificanceKCa3.1-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.

Activation of KCa3.1 by SKA‐31 induces arteriolar dilatation and lowers blood pressure in normo‐ and hypertensive connexin40‐deficient mice

“…As SKA-31 is able to penetrate the brain, activation of these channels may induce inhibition of neural activation. In fact, SKA-31 exerts a sedative effect at higher dosages, which is independent of KCa3.1 because it was also observed in animals deficient in KCa3.1 (Lambertsen et al, 2012). Thus, we suggest that the bradykardia observed at the highest SKA-31 dosage in mice is probably due to activation of KCa2 channels through an effect on pacemaker tissue in conjunction with a potential sedative effect.…”

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

“…This method provides accurate assessments of total tissue mass (g), bone mineral density (BMD, g/cm 2 ), bone mineral content (BMC, g), bone area (cm 2 ), fat mass (g), % fat tissue and lean tissue mass (g). 45 Behavioral assessments…”

“…Spontaneous alternation behavior and hence working memory was tested using the Y-maze test in naive mTNF Á/Á and mTNF wt/wt as previously described. 45 Each mouse was placed in the arm designated (A) of the Y-maze field. Except for the first two, the number of entries into each arm (A, B, C) was recorded manually over an 8 min period and spontaneous alternation calculated based on these numbers (n ¼ 6 mice/group (mTNF Á/Á and mTNF wt/wt ) and n ¼ 15-18/group (TNF À/À and WT)).…”

The water channel aquaporin-1 contributes to renin cell recruitment during chronic stimulation of renin production

“…The homogenate was centrifuged twice, first in 2.0-ml tubes (3,000 rpm, 10 min at 4°C), and then after transfer of the unclear supernatant to 1.5-ml tubes, PCA extracts were centrifuged again (12,000 rpm, 5 min at 4°C). The norepinephrine content of the clear supernatant was determined by HPLC with electrochemical detection, essentially as previously described (19,22). PCA extracts of kidneys were diluted 50 times in the mobile phase before injection (5 or 10 l) into the HPLC system.…”