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Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na V 1.2 and Na V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na V channels that exhibit state-dependent block of both Na V 1.2 and Na V 1.6, along with knock-in mice with changes in Na V 1.2 or Na V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na V 1.2 and Na V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action potential output, with Na V 1.6 block decreasing and Na V 1.2 block increasing output. Thus, Na V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na V isoform blockade.

Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na V 1.2 and Na V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na V channels that exhibit state-dependent block of both Na V 1.2 and Na V 1.6, along with knock-in mice with changes in Na V 1.2 or Na V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na V 1.2 and Na V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action potential output, with Na V 1.6 block decreasing and Na V 1.2 block increasing output. Thus, Na V isoforms have unique roles in regulating different aspects of pyramidal cell excitability, and our work may help guide the development of therapeutics designed to temper hyperexcitability through selective Na V isoform blockade.

The limbic system is presumed to have a central role in cognitive performance, in particular memory. The purpose of this study was to investigate the relationship between limbic white matter microstructure and neuropsychological function in temporal-lobe epilepsy (TLE) patients using diffusion tensor imaging (DTI). Twenty-one adult TLE patients, including 7 non-lesional (nlTLE) and 14 with unilateral mesial temporal sclerosis (uTLE), were studied with both DTI and hippocampal T2 relaxometry. Correlations were performed between fractional anisotropy (FA) of the bilateral fornix and cingulum, hippocampal T2, neuropsychological tests. Positive correlations were observed in the whole group for the left fornix and processing speed index. In contrast, memory tests did not show significant correlations with DTI findings. Subgroup analysis demonstrated an association between the left fornix and processing speed in nlTLE but not uTLE. No correlations were observed between hippocampal T2 and test scores in either the TLE group as a whole or after subgroup analysis. Our findings suggest that integrity of the left fornix specifically is an important anatomical correlate of cognitive function in TLE patients, in particular patients with nlTLE.