Identification and molecular mechanisms of the rapid tonicity-induced relocalization of the aquaporin 4 channel

The aquaporin family of integral membrane proteins is comprised of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically-driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves protein kinase A (PKA) activation, influx of extracellular calcium and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine- 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain oedema

Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders.

Objective Erythropoietin (EPO) improves verbal memory and reverses sub-field hippocampal volume loss across depression and bipolar disorder. This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort. Method Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or bipolar disorder in remission were randomized to eight weekly erythropoietin (40,000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by post-scan recall. Results Sixty-two patients had complete data (EPO: N=32, saline: N=30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure or medication. Conclusion The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement. </p

Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders

Objective Erythropoietin (EPO) improves verbal memory and reverses sub-field hippocampal volume loss across depression and bipolar disorder. This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort. Method Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or bipolar disorder in remission were randomized to eight weekly erythropoietin (40,000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by post-scan recall. Results Sixty-two patients had complete data (EPO: N=32, saline: N=30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure or medication. Conclusion The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement. </p