Regulation of KCa2.3 andendothelium-dependent hyperpolarization (EDH) in the rat middle cerebral artery: the role of lipoxygenase metabolites and isoprostanes

Background and Purpose. In rat middle cerebral arteries, endothelium-dependent hyperpolarization (EDH) is mediated by activation of calcium-activated potassium(KCa) channels specifically KCa2.3 and KCa3.1. Lipoxygenase (LOX) products function as endothelium-derived hyperpolarizing factors (EDHFs) in rabbit arteries by stimulating KCa2.3. We investigated if LOX products contribute to EDH in rat cerebral arteries. Methods. Arachidonic acid (AA) metabolites produced in middle cerebral arteries were measured using HPLC and LC/MS. Vascular tension and membrane potential responses to SLIGRL were simultaneously recorded using wire myography and intracellular microelectrodes. Results. SLIGRL, an agonist at PAR2 receptors, caused EDH that was inhibited by a combination of KCa2.3 and KCa3.1 blockade. Non-selective LOX-inhibition reduced EDH, whereas inhibition of 12-LOX had no effect. Soluble epoxide hydrolase (sEH) inhibition enhanced the KCa2.3 component of EDH. Following NO synthase (NOS) inhibition, the KCa2.3 component of EDH was absent. Using HPLC, middle cerebral arteries metabolized 14C-AA to 15- and 12-LOX products under control conditions. With NOS inhibition, there was little change in LOX metabolites, but increased F-type isoprostanes. 8-iso-PGF2α inhibited the KCa2.3 component of EDH. Conclusions. LOX metabolites mediate EDH in rat middle cerebral arteries. Inhibition of sEH increases the KCa2.3 component of EDH. Following NOS inhibition,loss of KCa2.3 function is independent of changes in LOX production or sEH inhibition but due to increased isoprostane production and subsequent stimulation of TP receptors. These findings have important implications in diseases associated with loss of NO signaling such as stroke; where inhibition of sEH and/or isoprostane formation may of benefit.

Right hemisphere language functions and schizophrenia: the forgotten hemisphere?

This review highlights the importance of right hemisphere language functions for successful social communication and advances the hypothesis that the core deficit in psychosis is a failure of segregation of right from left hemisphere functions. Lesion studies of stroke patients and dichotic listening and functional imaging studies of healthy people have shown that some language functions are mediated by the right hemisphere rather than the left. These functions include discourse planning/comprehension, understanding humour, sarcasm, metaphors and indirect requests, and the generation/comprehension of emotional prosody. Behavioural evidence indicates that patients with typical schizophrenic illnesses perform poorly on tests of these functions, and aspects of these functions are disturbed in schizo-affective and affective psychoses. The higher order language functions mediated by the right hemisphere are essential to an accurate understanding of someone's communicative intent, and the deficits displayed by patients with schizophrenia may make a significant contribution to their social interaction deficits. We outline a bi-hemispheric theory of the neural basis of language that emphasizes the role of the sapiens-specific cerebral torque in determining the four-chambered nature of the human brain in relation to the origins of language and the symptoms of schizophrenia. Future studies of abnormal lateralization of left hemisphere language functions need to take account of the consequences of a failure of lateralization of language functions to the right as well as the left hemisphere.

Increased protein SUMOylation following focal cerebral ischemia

Stroke is a major cause of death and disability, which involves excessive glutamate receptor activation leading to excitotoxic cell death. We recently reported that SUMOylation can regulate kainate receptor (KAR) function. Here we investigated changes in protein SUMOylation and levels of KAR and AMPA receptor subunits in two different animal stroke models: a rat model of focal ischemia with reperfusion and a mouse model without reperfusion. In rats, transient middle cerebral artery occlusion (MCAO) resulted in a striatal and cortical infarct. A dramatic increase in SUMOylation by both SUMO-1 and SUMO-2/3 was observed at 6h and 24h in the striatal infarct area and by SUMO-2/3 at 24h in the hippocampus, which was not directly subjected to ischemia. In mice, permanent MCAO resulted in a selective cortical infarct. No changes in SUMOylation occurred at 6h but there was increased SUMO-1 conjugation in the cortical infarct and non-ischemic hippocampus at 24h after MCAO. Interestingly, SUMOylation by SUMO-2/3 occurred only outside the infarct area. In both rat and mouse levels of KARs were only decreased in the infarct regions whereas AMPARs were decreased in the infarct and in other brain areas. These results suggest that posttranslational modification by SUMO and down-regulation of AMPARs and KARs may play important roles in the pathophysiological response to ischemia.

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay

In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC