Neuroscience
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Positive allosteric modulators (PAMs) of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors receive increasing interest as therapeutic drugs and have long served as important experimental tools in the study of the molecular mechanisms underlying glutamate-mediated neurotransmission. The aim of this study was to investigate functional and structural aspects of a novel analog of the AMPA receptor PAM cyclothiazide (CTZ) on recombinant and native glutamate receptors. We expressed rat GluA4flip and flop in Xenopus oocytes and characterized NS1376 and CTZ under two-electrode voltage-clamp. ⋯ Finally, we obtained detailed molecular information through X-ray structures, docking and molecular dynamics, which revealed that NS1376 interacts at the dimer interface of the ligand-binding domain in a manner overall similar to CTZ. NS1376 reveals that minor structural changes in CTZ can result in an altered modulatory profile, both enhancing agonist efficacy while markedly reducing agonist potency. These unique properties add new aspects to the complexity of allosteric modulations in neuronal systems.
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Contrast adaptation, generated by prolonged viewing of a high contrast spatial pattern, is known to reduce perceptual sensitivity to subsequently presented stimuli of similar spatial frequency (SF). Neural correlates of this pattern-specific contrast adaptation have been described in several classic studies in cat primary visual cortex (V1). ⋯ We found that adapting stimuli that drove a neuron more strongly generally produced more adaptation, implicating an intrinsic or fatigue-like process. Importantly, we also observed that slightly stronger contrast adaptation was produced when the adapting SF matched the test SF even when matched and nonmatched adapting gratings elicited similar spike rates indicating extrinsic or network processes contribute as well.
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The 5-HT6 receptor (5-HT6R) is almost exclusively expressed in the brain and has emerged as a promising target for cognitive disorders, including Alzheimer's disease. In the present study, we have determined the cell types on which the 5-HT6R is expressed by colocalizing 5-HT6R mRNA with that of a range of neuronal and interneuronal markers in the rat brain. Here, we show that 5-HT6R mRNA was expressed at high levels in medium spiny neurons in caudate putamen and in nucleus accumbens, as well as in the olfactory tubercle. ⋯ Serotonergic, dopaminergic or cholinergic neurons did not express 5-HT6R mRNA. These data indicate that the 5-HT6R is located on GABAergic and glutamatergic principal neurons, and on a subset of interneurons mainly belonging to the 5-HT3aR subgroup suggesting that the 5-HT6R is positioned to regulate the balance between excitatory and inhibitory signaling in the brain. These data provide new insights into the mechanisms of 5-HT6R signaling.