Brain Expression of Kv3 Subunits During Development, Adulthood and Aging and in a Murine Model of Alzheimer’s Disease

Abstract

In neurons, voltage-dependent Kv3 potassium channels are essential for the generation of action potentials at high frequency. A dysregulation of the Kv3.1 and Kv3.4 channel subunits has been suggested to contribute to neuronal and glial alterations in Alzheimer's disease, but a quantitative evaluation of these subunits in a mouse model of the pathology is still lacking. We analysed the profile of expression of the four Kv3 subunits by quantitative reverse transcription PCR and Western blot in the whole mouse brain and in dissected brain regions (olfactory bulb, septum, neocortex, hippocampus, brainstem and cerebellum) from 14 days after conception to 18 months after birth. In addition, we measured the levels of Kv3.1 and Kv3.4 messenger RNAs (mRNAs) and proteins in neocortex and hippocampus of APPPS1 mice, a transgenic model of Alzheimer's disease. Although all Kv3 transcripts were significantly expressed in embryonic age in whole brain extracts, only Kv3.1, Kv3.2 and Kv3.4 subunit proteins were present, suggesting a novel role for Kv3 channels at this developmental stage. With the exception of Kv3.4, during postnatal development, Kv3 transcripts and proteins showed a progressive increase in expression and reached an asymptote in adulthood, suggesting that the increase in Kv3 expression during development might contribute to the maturation of the electrical activity of neurons. During aging, Kv3 expression was rather stable. In contrast, in the neocortex of aged APPPS1 mice, Kv3.1 mRNA and protein levels were significantly lower compared to wild type, suggesting that a decrease in Kv3 currents could play a role in the cognitive symptoms of Alzheimer's disease.

ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

“…, Epha4 [40], Scn1a [41], and Kcnc1 [42]. Protein detection by immunoblot was used to validate some of the microarray gene expression data with different cohorts of mice.…”

Kv3.4 is modulated by HIF-1α to protect SH-SY5Y cells against oxidative stress-induced neural cell death

“…They demonstrated that highly elevated ROS levels are found in the aging brain and in many neurodegenerative diseases and therefore, oxidative modification of K + channels might be a general principle underlying aging and neurodegeneration 56 . Kv3.4 has been suggested as a new therapeutic target for major neurodegenerative diseases, and the mechanisms of Kv3.4 related to these diseases have been investigated 14, 57 . However, the relationship between the oxidative modification of Kv3.4 and neurodegenerative diseases remains unknown.…”

Potassium Channels: Structures, Diseases, and Modulators

“…Analysis of gene expression throughout the different stages of AD suggests that up-regulation of Kv3.4 (KCNC4) and dysregulation of Kv3.1 (KCNC1) alter potassium currents in neurons and leads to altered synaptic activity that may underlie the neurodegeneration observed in AD (165). While in contrast, in the neocortex of aged APPPS1 mice, Kv3.1 mRNA and protein levels were significantly lower compared to wild type, suggesting that a decrease in Kv3 currents could play a role in the cognitive symptom s of Alzheimer 's disease (166). While in contrast, in the neocortex of aged APPPS1 mice, Kv3.1 mRNA and protein levels were significantly lower compared to wild type, suggesting that a decrease in Kv3 currents could play a role in the cognitive symptom s of Alzheimer 's disease (166).…”