Cortical fast-spiking (FS) neurons generate high-frequency action potentials (APs) without apparent frequency accommodation, thus providing fast and precise inhibition. However, the maximal firing frequency that they can reach, particularly in primate neocortex, remains unclear. Here, by recording in human, monkey, and mouse neocortical slices, we revealed that FS neurons in human association cortices (mostly temporal) could generate APs at a maximal mean frequency (Fmean) of 338 Hz and a maximal instantaneous frequency (Finst) of 453 Hz, and they increase with age. The maximal firing frequency of FS neurons in the association cortices (frontal and temporal) of monkey was even higher (Fmean 450 Hz, Finst 611 Hz), whereas in the association cortex (entorhinal) of mouse it was much lower (Fmean 215 Hz, Finst 342 Hz). Moreover, FS neurons in mouse primary visual cortex (V1) could fire at higher frequencies (Fmean 415 Hz, Finst 582 Hz) than those in association cortex. We further validated our in vitro data by examining spikes of putative FS neurons in behaving monkey and mouse. Together, our results demonstrate that the maximal firing frequency of FS neurons varies between species and cortical areas.
The dissolution rate and the oral bioavailability of nitrendipine were significantly affected by the crystal size, and the oral bioavailability could be improved significantly by preparing it as nanocrystals. FaSSIF can be used to predict differences in oral absorption of crystals with different particle sizes.
Na v 1.8 is a tetrodotoxin-resistant voltage-gated sodium channel selectively expressed in primary sensory neurons. Peripheral inflammation and nerve injury induce Na v 1.8 accumulation in peripheral nerves. However, the mechanisms and related significance of channel accumulation in nerves remains unclear. Here we report that KIF5B promotes the forward transport of Na v 1.8 to the plasma membrane and axons in dorsal root ganglion (DRG) neurons of the rat. In peripheral inflammation induced through the intraplantar injection of complete Freund's adjuvant, increased KIF5 and Na v 1.8 accumulation were observed in the sciatic nerve. The knock-down of KIF5B, a highly expressed member of the KIF5 family in DRGs, reduced the current density of Na v 1.8 in both cultured DRG neurons and ND7-23 cells. Overexpression of KIF5B in ND7-23 cells increased the current density and surface expression of Na v 1.8, which were abolished through brefeldin A treatment, whereas the increases were lost in KIF5B mutants defective in ATP hydrolysis or cargo binding. Overexpression of KIF5B also decreased the proteasome-associated degradation of Na v 1.8. In addition, coimmunoprecipitation experiments showed interactions between the N terminus of Na v 1.8 and the 511-620 aa sequence in the stalk domain of KIF5B. Furthermore, KIF5B increased Na v 1.8 accumulation, Na v 1.8 current, and neuronal excitability detected in the axons of cultured DRG neurons, which were completely abolished by the disruption of interactions between KIF5B and the N terminus of Na v 1.8. Therefore, our results reveal that KIF5B is required for the forward transport and axonal function of Na v 1.8, suggesting a mechanism for axonal accumulation of Na v 1.8 in inflammatory pain.
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