Journal of Neurochemistry最新文献

Microglia are crucial for brain development and their function can be impacted by postnatal insults, such as early-life allergies. These are characterized by an upregulation of interleukin (IL)-4 levels. Allergies share a strong comorbidity with Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). We previously showed that early-life allergic asthma induces hyperactive and impulsive behaviors in mice. This phenotype was reproduced in animals administered with IL-4 in the second postnatal week. Mechanistically, elevated IL-4 levels prevented microglia-mediated engulfment of neurons in the cerebellum, resulting in a surplus of granule cells and consequent dysfunction in cerebellar connectivity. Here, we aimed to further understand the impact of early IL-4 administration in microglia of the cerebellum and the prefrontal cortex (PFC), two brain regions with protracted developmental programs and susceptible to immune system malfunction after birth. While IL-4 administration induced differential short-term effects on microglia in the cerebellum and PFC, both regions presented similar microglial features in adult mice. Although Sholl analysis did not reveal significant alterations in overall microglia morphology at postnatal day (P)10, the density of microglia was decreased in the cerebellum at this age, especially in the granular layer (GL), but remained unaltered in the PFC. Interestingly, the presence of microglia with phagocytic cups, morphological features important for whole-cell engulfment, was decreased in both regions. When assessing the long-term consequences of IL-4 administration, cerebellar and PFC microglia were hypo-ramified and exhibited increased overall density. Importantly, microglia alterations were exclusive to the GL of the cerebellum and the infralimbic region of the PFC. Our results show that postnatal elevated levels of IL-4 impair the percentage of microglia engaged in cell clearing in two brain regions with protracted developmental programs. Interestingly, IL-4-exposed microglia adapt a similar phenotype in the adult cerebellum and PFC. Our data suggest that this early-life increase in IL-4 levels is sufficient to elicit long-lasting alterations in microglia, potentially increasing cell susceptibility to later insults.

Preclinical behavioral testing is essential for drug discovery in neuropsychiatric disorders, yet translational challenges persist because of interspecies differences. Touchscreen-based behavioral tasks offer a promising solution for bridging this gap. These tasks provide flexibility across cognitive domains and species, facilitating rigorous comparisons. They complement traditional assays, offering improved face, predictive, and construct validity by mirroring human neuropsychological tests. Notably, nearly identical tasks have been validated in multiple species, enhancing translational potential. Recent studies demonstrate conserved neurocircuitry engagement in touchscreen tasks, supporting their relevance to human function and therapeutic development. The integration of electrophysiological measures, such as electroencephalography (EEG) and local field potential (LFP) recordings with touchscreen behavioral assays, enhances translational biomarker discovery and serves to elucidate neural circuit dynamics. Despite current limitations and the need for further validation, this approach offers a pathway to more efficient drug discovery. This review covers recent research describing the feasibility and benefits of EEG/LFP-touchscreen combination studies in rodents. While the field is still in its early stages, the promise of this research strategy is evident. Future efforts will likely focus on refining methodologies, identifying robust translational biomarkers, and expanding studies across species. Touchscreen-based platforms, integrated with electrophysiological measurements, hold significant potential to advance our understanding of neuropsychiatric disorders and accelerate the development of effective treatments.

Neuron–glia interactions are fundamental to the development and function of the nervous system. During development, glia, including astrocytes, microglia, and oligodendrocytes, influence neuronal differentiation and migration, synapse formation and refinement, and myelination. In the mature brain, glia are crucial for maintaining neural homeostasis, modulating synaptic activity, and supporting metabolic functions. Neurons, inherently vulnerable to various stressors, rely on glia for protection and repair. However, glia, in their reactive state, can also promote neuronal damage, which contributes to neurodegenerative and neuropsychiatric diseases. Understanding the dual role of glia—as both protectors and potential aggressors—sheds light on their complex contributions to disease etiology and pathology. By appropriately modulating glial activity, it may be possible to mitigate neurodegeneration and restore neuronal function. In this review, which originated from the International Society for Neurochemistry (ISN) Advanced School in 2019 held in Montreal, Canada, we first describe the critical importance of glia in the development and maintenance of a healthy nervous system as well as their contributions to neuronal damage and neurological disorders. We then discuss potential strategies to modulate glial activity during disease to protect and promote a properly functioning nervous system. We propose that targeting glial cells presents a promising therapeutic avenue for rebuilding the nervous system.

One standing challenge for Alzheimer's disease (AD) research is early diagnosis, which provides a time window for early intervention. Sharmin et al recently reported a positive association between plasma ptau181 and plasma metabolites, medium- and long-chain acylcarnitines (ACs) in both cognitively normal (CN) Aβ− and CN Aβ+ older adults, suggesting a link between initial Aβ pathology and acylcarnitine-mediated energy metabolism pathways. Consistently, ACs could classify PET-Aβ status in elderly individuals. This study has provided further clues for early biomarker searching for AD, linking metabolic pathways with AD pathogenesis.

Neurotransmitter:sodium symporters (NSS) reuptake neurotransmitter molecules from the synaptic space through Na⁺-coupled transport. They are thought to work via the alternating access mechanism, exploring multiple configurations dictated by the binding of substrates and ions. Much of the current knowledge about these transporters has been derived from examining the structure of the Leucine Transporter (LeuT), a bacterial counterpart to human NSSs. Multiple crystal structures of LeuT provided valuable information regarding the steps involved in this mechanism. Dynamical data connecting the crystal structure to the transport cycle are critical to understanding how ligands are translated through the membrane. In the present study, we applied ¹⁹F-based nuclear magnetic resonance (NMR) spectroscopy to ¹⁹F labelled LeuT to monitor how substrates and ions binding affect the conformations of the transporter. By selecting mutations and ligands known to affect the conformational equilibrium of LeuT, we identified and assigned four NMR resonances to specific conformational states of LeuT. We observe that Na⁺ ions produce closure of the extracellular vestibule to a state similarly induced by Na⁺ and substrates. Conversely, K⁺ ions seem to shift the conformational equilibrium toward inward-facing intermediates, arguably by competing with Na⁺. The present study assembles a framework for NMR-based dynamical studies of NSS transporters and demonstrates its feasibility for tackling large membrane LeuT-fold transporters.

Sleep is vital for maintaining physical and mental well-being, impacting cognitive functions like memory and learning through neuroplasticity. Sleep disturbances prevalent in neurological and psychiatric disorders exacerbate cognitive decline, imposing societal burdens. Exploring the relationship between sleep and neuroplasticity elucidates the mechanisms influencing cognition, particularly amidst the prevalent sleep disturbances in these clinical populations. While existing reviews provide valuable insights, gaps remain in understanding the neurophysiological mechanisms underlying sleep and cognitive function. This scoping review aims to investigate the characteristic patterns of sleep parameters and neurochemical biomarkers in reflecting neuroplasticity changes related to neurological and psychiatric disorders and to explore how these markers interact and influence cognition at the molecular level. Studies involving adults and older adults were included, excluding animal models and the paediatric population. Selected studies explored the relationship between sleep parameter or neurochemical biomarker changes and cognitive impairment, reflecting underlying neuroplasticity changes. Peer-reviewed articles, clinical trials, theses, and dissertations in English were included while excluding secondary research and non-peer-reviewed sources. A three-step search strategy was executed following the updated Joanna Briggs Institute methodology for scoping reviews. Published studies were retrieved from nine databases, grey literature, expert recommendations, and hand-searching of the included studies' bibliography. A basic qualitative content synthesis of 34 studies was conducted per JBI's scoping review guidance. Slow-wave and Rapid-Eye Movement sleep, sleep spindles, sleep cycle disruption, K-Complex(KC) density, Hippocampal sEEG, BDNF, IL-6, iNOS mRNA expression, plasma serotonin, CSF Aβ-42, t-tau and p-tau proteins, and serum cortisol revealed associations with cognitive dysfunction. Examining the relationship between sleep parameters, neurochemical biomarkers, and cognitive function reveals neuronal mechanisms that guide potential therapeutic interventions and enhance quality patient care.

Neuronal growth regulator 1 (NEGR1) is a synaptic plasma membrane localized cell adhesion molecule implicated in a wide spectrum of psychiatric disorders. By RNAseq analysis of the transcriptomic changes in the brain of NEGR1-deficient mice, we found that NEGR1 deficiency affects the expression of the Gad2 gene. We show that glutamic acid decarboxylase 65 (GAD65), the Gad2 - encoded enzyme synthesizing the inhibitory neurotransmitter GABA on synaptic vesicles, accumulates non-synaptically in brains of NEGR1-deficient mice. The density of non-synaptic GAD65 accumulations is also increased in NEGR1 deficient cultured hypothalamic neurons, and this effect is rescued by re-expression of NEGR1. By using a novel biosensor of the plasma membrane attachment of GAD65, we demonstrate that GAD65 attaches to the plasma membrane. NEGR1 promotes palmitoylation-dependent clearance of GAD65 from the plasma membrane and targeting of GAD65 to plasma membrane-derived endocytic vesicles. In NEGR1 deficient cultured hypothalamic neurons, the synaptic and extrasynaptic levels of the plasma membrane attached GAD65 are increased, and the synaptic levels of GABA are reduced. NEGR1-deficient mice are characterized by reduced body weight, lower GABAergic synapse densities in the arcuate nucleus, and blunted responsiveness to the reinforcing effects of food rewards. Our results indicate that abnormalities in synaptic GABA synthesis can contribute to brain disorders associated with abnormal expression of NEGR1 in humans.

To date, several studies have integrated genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data from bulk tissues to identify novel Alzheimer's disease (AD) genetic variants and susceptibility genes. However, there is highly cell-type-specific nature in different bulk eQTL data. Until now, eQTL data from different brain single cells have been reported. Therefore, integrating eQTL data from different brain single-cell types along with AD GWAS data makes biological sense for studying the potential biological explanations of AD. Here, we utilized the summary-data-based Mendelian randomization (SMR) method to integrate AD GWAS data with eQTL data from eight brain single-cell types. We identified a larger number of significant genes compared to previous SMR study based on bulk eQTL. Notably, microglia exhibited the highest number of significant genes. Moreover, we conducted validation-phase SMR analysis, single-cell analysis, protein–protein interaction (PPI), druggability evaluation, functional enrichment analyses, and colocalization analysis of the top 20 SMR significant genes in microglia. We found that most genes passed the validation and were significantly enriched in microglia. PPI analysis uncovered interactions among PICALM, BIN1, RIN3, CD2AP, CASS4, and MS4A6E. Five most significant SMR genes were further validated through colocalization analysis. RIN3 is the only significant gene across all mentioned analyses and is a novel AD susceptibility gene at the genome-wide significance level. Druggability evaluation identified KCNQ3, HLA-DQB1, and RABEP1 as known genes previously targeted for drug development in neurological disorders, suggesting their potential therapeutic relevance in AD.

The dopamine (DA) transporter (DAT) is a major determinant of DAergic neurotransmission, and is a primary target for addictive and therapeutic psychostimulants. Evidence accumulated over decades in cell lines and in vitro preparations revealed that DAT function is acutely regulated by membrane trafficking. Many of these findings have recently been validated in vivo and in situ, and several behavioral and physiological findings raise the possibility that regulated DAT trafficking may impact DA signaling and DA-dependent behaviors. Here we review key DAT trafficking findings across multiple systems, and discuss the cellular mechanisms that mediate DAT trafficking, as well as the endogenous receptors and signaling pathways that drive regulated DAT trafficking. We additionally discuss recent findings that DAT trafficking dysfunction correlates to perturbations in DA signaling and DA-dependent behaviors.

Neurotransmitter transporters (NTTs) control synaptic responses by modulating the concentration of neurotransmitters at the synaptic cleft. Glutamate is the most abundant excitatory neurotransmitter in the brain and needs to be finely tuned in time and space to maintain a healthy brain and precise neurotransmission. The glutamate transporter EAAT2 (SLC1A2) is primarily responsible for glutamate clearance. EAAT2 impairment has been associated with Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both monogenic and sporadic forms of PD, of which the common substitution Gly2019Ser is associated with a significant deficit in EAAT2 expression. The role of pathological mutants of the LRRK2 is intensively studied and reviewed. Here we have focused the attention on the physiological role of LRRK2 on EAAT2, comparing the activity of NTTs with or without the LRRK2 kinase. By heterologous expression in Xenopus laevis oocytes and two-electrode voltage clamp, the current amplitudes of the selected NTTs and kinetic parameters have been collected in the presence and absence of LRRK2. The results show that EAAT2 expression and function are impaired in the absence of the kinase and also under its pharmacological inhibition via MLi-2 treatment. LRRK2 stabilizes EAAT2 expression increasing the amount of transporter at the plasma membrane. Interestingly, the LRRK2 action is EAAT2-specific, as we observed no significant changes in the transport current amplitude and kinetic parameters obtained for the other excitatory and inhibitory NTTs studied. This study, for the first time, demonstrates the physiological importance of LRRK2 in EAAT2 function, highlighting the specificity of LRRK2-mediated modulation of EAAT2 and suggesting a potential role for the kinase as a checkpoint for preserving neurons from excitotoxicity. In brain conditions associated with impaired glutamate clearance, targeting LRRK2 for EAAT2 regulation may offer novel therapeutic opportunities.