Neuroscience
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Previous studies have indicated that presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) contribute to the regulation of neurotransmitter release. In hippocampal synapses, the presynaptic surface expression of several AMPAR subunits, including GluA2, is regulated in a ligand-dependent manner. However, the molecular mechanisms underlying the presynaptic trafficking of AMPARs are still unknown. ⋯ Furthermore, we show that GluA2 and protein interacting with C kinase 1 (PICK1) are colocalized at presynaptic vesicles. Similar to postsynaptic mechanisms, overexpression of either PICK1 or pep2m, which inhibit the N-ethylmaleimide sensitive fusion protein (NSF)-GluA2 interaction, decreases the concentration of GluA2 in the presynaptic active zone membrane. These data suggest that the interacting proteins PICK1 and NSF act as regulators of presynaptic GluA2-containing AMPAR trafficking between the active zone and a vesicle pool that may provide the basis of presynaptic components of synaptic plasticity.
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It was postulated that neuropeptide Y (NPY)-ergic system could be involved in the ischemic pathophysiology, however, the role of particular subtypes of NPY receptors (YRs) in neuroprotection against ischemia is still not well known. Therefore, we investigated the effect of NPY and YR ligands using in vitro and in vivo experimental ischemic stroke models. Our in vitro findings showed that NPY (0.5-1μM) and specific agonists of Y2R (0.1-1μM) and Y5R (0.5-1μM) but not that of Y1R produced neuroprotective effects against oxygen-glucose deprivation (OGD)-induced neuronal cell death, being also effective when given 30min after the end of OGD. ⋯ Data from in vivo studies demonstrated that Y2R agonist (10μg/6μl; i.c.v.) not only diminished the infarct volume in rats subjected to transient middle cerebral artery occlusion (MCAO) but also improved selected gait parameters in CatWalk behavioral test, being also effective after delayed treatment. Moreover, we found that a Y5R agonist (10μg/6μl; i.c.v.) did not reduce MCAO-evoked brain damage but improved stride length, when it was given 30min after starting the occlusion. In conclusion, our studies indicate that Y5 and especially Y2 receptors may be promising targets for neuroprotection against ischemic damage.
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About 7.5million adults in Germany cannot read and write properly despite attending school for several years. They are considered to be functional illiterates. Since the ability to read and write is crucial for being employed and socially accepted, we developed a literacy training to overcome these deficits. ⋯ Moreover, the increase was positively correlated with reading and writing skills. The findings suggest that poor literacy skills are associated with several structural abnormalities in reading-related brain areas. In addition, we showed that while literacy skills of functional illiterates improved after training, the structural differences to controls disappeared.
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Cysteine protease Cathepsin S (CatS) expressed by spinal microglia has been shown to play a critical role in nerve injury and inflammation-induced chronic pain. However, whether microglial CatS contributes to remifentanil-induced acute hyperalgesia remains unstudied. In the present study, intravenous remifentanil infusion induced a significant increase in the expression of premature and mature form of CatS in the activated microglia in the spinal cord. ⋯ However, increased protein level of premature form of CatS was not affected by PBN. Altogether, our findings demonstrate that neuronal ROS promote maturation of microglial CatS which facilitates activation of NMDA in the spinal dorsal horn. Therefore, such mechanism is involved in neuron-microglia positive feedback and contributes to remifentanil-induced hyperalgesia.
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Mutations in the Pejvakin (Pjvk) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. ⋯ Using the C-terminal domain of pejvakin as bait, we identified in a cochlear cDNA library ROCK2, an effector for the small GTPase Rho, and the scaffold protein IQGAP1, involved in modulating actin dynamics. Both ROCK2 and IQGAP1 associate via their coiled-coil domains with pejvakin. We conclude that pejvakin is required to sustain OHC activity and survival in a cell-autonomous manner likely involving regulation of Rho signaling.