Neuroscience
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Increasing evidence has linked membrane cholesterol to amyloid precursor protein (APP) processing. β-Sitosterol (BS) is one of the most common forms of plant sterols, with the structure very similar to that of cholesterol. Using HT22 mouse hippocampal cells, this study investigated whether the substitution of membrane cholesterol with BS influences APP metabolism. ⋯ Additional experiments suggest that the effect of membrane BS on APP metabolism is associated with the migration of APP from lipid rafts toward non-raft regions. Given that dietary BS can enter the brain and accumulates in the plasma membrane of brain cells, these results suggest a potential use of BS in the prevention of Alzheimer's disease.
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Cortical spontaneous activity reflects an animal's behavioral state and affects neural responses to sensory stimuli. The correlation between excitatory and inhibitory synaptic input to single neurons is a key parameter in models of cortical circuitry. Recent measurements demonstrated highly correlated synaptic excitation and inhibition during spontaneous "up-and-down" states, during which excitation accounted for approximately 80% of inhibitory variance (Shu et al., 2003; Haider et al., 2006). ⋯ Excitation and inhibition are weakly correlated, relative to the up-and-down state: excitation accounts for less than 40% of inhibitory variance. Although these correlations are lower than when the circuit cycles between up-and-down states, both behaviors may arise from the same circuitry. Our observations provide evidence that different correlational patterns of excitation and inhibition underlie different cortical states.
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Various protein motifs play a key role in regulating protein biogenesis and trafficking. Here, we discovered that three distinct motifs regulate the trafficking of acid-sensing ion channel 1a (ASIC1a), the primary neuronal proton receptor which plays critical roles in neurological diseases including stroke, multiple sclerosis and seizures. Mutating the PDZ binding motif of ASIC1a increased its surface expression and current density. ⋯ These changes were likely due to a change in ASIC1a biogenesis; mutating either the RRGK or KEAKR motif reduced N-glycosylation of ASIC1a while mutating the PDZ binding motif had the opposite effect. Our results demonstrate that these C-terminal motifs are important for ASIC1a trafficking and channel function. In addition, in contrast to multiple previous studies, which all show that K/R containing motifs lead to endoplasmic reticulum (ER) retention, our findings indicate that these motifs can also be required for efficient trafficking.
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Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. ⋯ Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI.
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Schizophrenia is a severe condition that has been associated with functional abnormalities in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides modulate the activity of VTA DA neurons and might be involved in DA abnormalities relevant to schizophrenia. Recent work from our lab showed that systemic injection of the dopamine D1/D2 receptor agonist apomorphine in rats, which mimics schizophrenia-like behaviors in humans, also evoked a redistribution of NK3Rs in DA neurons of the rat VTA. ⋯ In non-TH, presumably GABAergic neurons of the VTA, the NK3R densities in somata and dendrites were not significantly changed by apomorphine with or without SB222200. The results suggest that the NK3R antagonist SB222200 is effective against the apomorphine-evoked NK3R internalization in VTA DA dendrites, but does not prevent nuclear NK3R trafficking in VTA DA neurons. These results might have important implications in targeting NK3R antagonists in basic or clinical studies.