Expression of the kcnk3 potassium channel gene lessens the injury from cerebral ischemia, most likely by a general influence on blood pressure

7 p., 3 figures, 2 tables and references.We examined the possible protective effect of TASK-1 (TWIK-related acid-sensitive potassium channel-1, kcnk3) and -3 potassium channels during stroke. TASK-1 and TASK-3, members of the two pore domain (K2P or kcnk) potassium channel family, form hetero or homodimers and help set the resting membrane potential. We used male TASK-1 and TASK-3 knockout mice in a model of focal cerebral ischemia, permanent middle cerebral artery occlusion (pMCAO). Infarct volume was measured 48 h after pMCAO. The TASK-1 knockout brains had larger infarct volumes (P=0.004), and those in TASK-3 knockouts were unchanged. As the TASK-1 gene is expressed in adrenal gland, heart and possibly blood vessels, the higher infarct volumes in the TASK-1 knockout mice could be due to TASK-1 regulating blood vessel tone and hence blood pressure or influencing blood vessel microarchitecture and blood flow rate. Indeed, we found that male TASK-1 knockout mice had reduced blood pressure, likely explaining the increased brain injury seen after pMCAO. Thus to make precise conclusions about how TASK-1 protects neurons, neural- or organ-specific deletions of the gene will be needed. Nevertheless, a consequence of having TASK-1 channels expressed (in various non-neuronal tissues and organs) is that neuronal damage is lessened when stroke occurs.Peer reviewe

Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction