The Journal of neuroscience : the official journal of the Society for Neuroscience
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Recent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. ⋯ Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory.
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Propofol is an intravenous general anesthetic that alters neuronal excitability by modulating agonist responses of pentameric ligand-gated ion channels (pLGICs). Evidence suggests that propofol enhancement of anion-selective pLGICs is mediated by a binding site between adjacent subunits, whereas propofol inhibition of cation-selective pLGICs occurs via a binding site contained within helices M1-M4 of individual subunits. We considered this idea by testing propofol modulation of homomeric human glycine receptors (GlyRs) and nematode glutamate-gated chloride channels (GluCls) recombinantly expressed in Xenopus laevis oocytes with electrophysiology. ⋯ Similarly, when the equivalent positions were examined in GlyRs, the M2 S18'I substitution significantly altered the maximum level of enhancement by propofol, and the M3 A288I substitution abolished propofol enhancement. These data are not consistent with separate binding sites for the opposing effects of propofol. Instead, these data suggest that propofol enhancement and inhibition are mediated by binding to a single site in anion-selective pLGICs, and the modulatory effect on channel gating depends on the M2 18' residue.
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Within neurons, mitochondria are nonuniformly distributed and are retained at sites of high activity and metabolic demand. Glutamate transport and the concomitant activation of the Na(+)/K(+)-ATPase represent a substantial energetic demand on astrocytes. We hypothesized that mitochondrial mobility within astrocytic processes might be regulated by neuronal activity and glutamate transport. ⋯ Inhibition of reversed Na(+)/Ca(2+) exchange also increased the percentage of mitochondria that were mobile. Last, we demonstrated that neuronal activity increases the probability that mitochondria appose GLT-1 particles within astrocyte processes, without changing the proximity of GLT-1 particles to VGLUT1. These results imply that neuronal activity and the resulting clearance of glutamate by astrocytes regulate the movement of astrocytic mitochondria and suggest a mechanism by which glutamate transporters might retain mitochondria at sites of glutamate uptake.
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In the current study we sought to dissociate the component processes of working memory (WM) (vigilance, encoding and maintenance) that may be differentially impaired in attention-deficit/ hyperactivity disorder (ADHD). We collected electroencephalographic (EEG) data from 52 children with ADHD and 47 typically developing (TD) children, ages 7-14 years, while they performed a spatial Sternberg working memory task. We used independent component analysis and time-frequency analysis to identify midoccipital alpha (8-12 Hz) to evaluate encoding processes and frontal midline theta (4-7 Hz) to evaluate maintenance processes. ⋯ Last, subjects with ADHD showed age-independent attenuation of evoked responses to warning cues, suggesting low vigilance. Combined, these three EEG measures predicted diagnosis with 70% accuracy. We conclude that the interplay of impaired vigilance and encoding in ADHD may compromise maintenance and lead to impaired WM performance in this group.
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Ongoing/spontaneous pain behavior is associated with ongoing/spontaneous firing (SF) in adult DRG C-fiber nociceptors (Djouhri et al., 2006). Causes of this SF are not understood. We show here that conducting (sometimes called uninjured) C-nociceptors in neuropathic pain models with more hyperpolarized resting membrane potentials (Ems) have lower SF rates. ⋯ After CFA-induced inflammation, spontaneous foot lifting (a measure of spontaneous pain) was (1) greater in rats with naturally lower TREK2 in ipsilateral small DRG neurons and (2) increased by siRNA-induced TREK2 knockdown in vivo. We conclude that TREK2 hyperpolarizes IB4 binding C-nociceptors and limits pathological spontaneous pain. Similar TREK2 distributions in small DRG neurons of several species suggest that these role(s) of TREK2 may be widespread.