Neuroscience
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The α3 Na+,K+-ATPase (α3NKA) is one of four known α isoforms of the mammalian transporter. A deficiency in α3NKA is linked to severe movement control disorders. Understanding the pathogenesis of these disorders is limited by an incomplete knowledge of α3NKA expression in the brain as well as the challenges associated with identifying living cells that express the isoform for subsequent electrophysiological studies. ⋯ Fluorescence was not detected in astrocytes or white matter areas. ZsGreen1-positive neurons were readily observed in fresh (unfixed) brain sections, which were amenable to patch-clamp recordings. Thus, the α3NKA-ZsGreen1 mouse model provides a powerful tool for studying the distribution and functional properties of α3NKA-expressing neurons in the brain.
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Microglia, the resident immune cells of the central nervous system (CNS), are activated at the beginning of the inflammatory response and induce detrimental neuroinflammation by producing excessive pro-inflammatory cytokines. Nuclear factor kappa B (NF-κB) signaling facilitates the onset of microglia activation. However, the molecular mechanisms underlying the negative regulation of NF-κB remain to be fully elucidated. ⋯ Co-immunoprecipitation experiments further revealed an interaction between H4R and tumor necrosis factor receptor-associated factor 6 (TRAF6) in microglia, which was verified both in vivo and in vitro. Our experimental results support our hypothesis that H4R interacts with TRAF6 to inhibit the release of inflammatory cytokines in LPS-induced microglia cells by decreasing TRAF6-mediated ubiquitination of K63. These findings provide theoretical and experimental evidence regarding the role of H4R in the microglia inflammatory response, which may aid in the development of novel treatments for inflammation.
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Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. Sensory-processing deficits are common in humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, manifesting in the auditory system as debilitating hypersensitivity and abnormal electroencephalographic (EEG) and event-related potential (ERP) phenotypes. FXS is a neurodevelopmental disorder, but how EEG/ERP phenotypes change during development is unclear. ⋯ Genotype differences in stimulus-evoked gamma power were present in both cortical regions, but the direction and strength of the changes were age-dependent. These findings suggest that cortical deficits are present during early development and may contribute to sensory-processing deficits in FXS, which in turn may lead to anxiety and delayed language. Developmental changes in EEG measures indicate that observations at a single time-point during development are not reflective of FXS disease progression and highlight the need to identify developmental trajectories and optimal windows for treatment.
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Preclinical evidence suggests that ketamine's rapid and sustained antidepressant actions are due to the induction of synaptogenesis in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP), two brain regions implicated in the pathophysiology of major depression. However, research on the neurobiological effects of ketamine has focused almost exclusively on males. Findings from our group and others indicate that female rodents are more reactive to ketamine's antidepressant effects, since they respond to lower doses in antidepressant-predictive behavioral models. ⋯ Ketamine activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in prefrontocortical synaptoneurosomes, and enhanced spine formation in the male mPFC and HIPP. In females, ketamine induced a sustained increase in hippocampal spine density. Overall, these data exposed a sharp sex difference in the synaptogenic response to ketamine in stress-naïve mice, and further suggest that the mPFC may play a more important role in mediating the antidepressant effects of the drug in males, while the HIPP may be more important for females.
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Peripheral diabetic neuropathy (PDN) manifests in 50-60% of type I and II diabetic patients and is the major cause of limb amputation. Adequate therapy for PDN is a current challenge. There are evidences that the activation of the P2X4 receptor (P2X4R) expressed on microglial cells of the central nervous system takes part in the development of neuropathic pain. ⋯ Finally, our study showed a functional expression of P2X4R in SGCs of the rat's DRG, because the P2X4R agonist BzATP elicits an increase in intracellular calcium concentration in SGCs, which was reduced by PSB-15417. These findings indicate that P2X4R activation in DRG is essential to diabetes-induced neuropathic mechanical hyperalgesia. Therefore, this purinergic receptor in DRG could be an interesting therapeutic target for quaternary P2X4R antagonists that do not cross the hematoencephalic barrier, for the control of neuropathic pain, preserving central nervous system functions.