Role of NKCC2A in Nervous system Activity

Abstract

The NKCC2A channel is a splice variant of the Na+K+2Cl‐ co‐transporter 2 (Slc12a1), which is abundantly expressed in macula densa and apical membrane of the tubular cells in the kidney but has not been reported in nervous tissue. This study was designed to determine if the NKCC2A absence altered behavior and nervous system activity in mice. NKCC2A wild type (WT), heterozygous (HE) and homozygous (HO) mice were tested in a behavioral battery in which there was a significant decrease in immobility in the Forced Swim Test (FST), a measure of depression‐like behavior. There were no differences in open field, Y‐maze, plus maze, pre‐pulse inhibition, functional observational battery or the rotarod test. Brain regions and adrenals were homogenized and catecholamines were measured using HPLC coupled to electrochemical detector. The serotonin metabolite to parent ratio in HE was elevated in rostral brainstem, significantly lower in the HO in the caudate nucleus with a non‐significant trend toward the same pattern in the amygdala. There was an increase in the intraneural but not the extraneural metabolite to parent ratio for dopamine. There were significantly lower levels of epinephrine and norepinephrine in the adrenals of HO, with the HE having intermediate levels. The pattern of results is consistent with the decreased immobility in the FST suggesting effects in brain areas involved in depressive‐like behavior. Further experiments will examine the biogenic amine use in nucleus accumbens, frontal cortex, hypothalamus, brain stem and urine. We will also employ a different test for depressive‐like behavior that has different false positives. These results implicate NKCC2A in brain and adrenal function in addition to its known role in the kidney.