Neuroglia (Basel, Switzerland)最新文献

Background/objectives: Compartmentalized glucose metabolism in the brain contributes to neuro-metabolic stability and shapes hypothalamic control of glucose homeostasis. Glucose transporter-2 (GLUT2) is a plasma membrane glucose sensor that exerts sex-specific control of hypothalamic astrocyte glucose and glycogen metabolism. Aging causes counterregulatory dysfunction.

Methods: Current research used Western blot and HPLC-electrospray ionization-mass spectrometry to investigate whether aging affects GLUT2-dependent hypothalamic astrocyte metabolic sensor and glycogen enzyme protein expression and glycogen mass according to sex.

Results: Data document GLUT2-dependent up-regulated glucokinase (GCK) protein in glucose-deprived old male and female astrocyte cultures, unlike GLUT2 inhibition of this protein in young astrocytes. Glucoprivation of old male and female astrocytes caused GLUT2-independent down-regulation of 5'-AMP-activated protein kinase (AMPK) protein, indicating loss of GLUT2 stimulation of this protein with age. This metabolic stress also caused GLUT2-dependent suppression of phospho-AMPK profiles in each sex, differing from GLUT2-mediated glucoprivic enhancement of activated AMPK in young male astrocytes and phospho-AMPK insensitivity to glucoprivation in young female cultures. GS and GP isoform proteins were refractory to glucoprivation of old male cultures, contrary to down-regulation of these proteins in young glucose-deprived male astrocytes. Aging elicited a shift from GLUT2 inhibition to stimulation of male astrocyte glycogen accumulation and caused gain of GLUT2 control of female astrocyte glycogen.

Conclusions: Outcomes document sex-specific, aging-related alterations in GLUT2 control of hypothalamic astrocyte glucose and ATP monitoring and glycogen mass and metabolism. Results warrant future initiatives to assess how these adjustments in hypothalamic astrocyte function may affect neural operations that are shaped by astrocyte-neuron metabolic partnership.

Background/objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST).

Methods: We analyzed the proteome in cortical-hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs).

Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated.

Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders.

Background: Chronic hypoperfusion is a risk factor for neurodegenerative diseases. However, the sequence of events driving ischemia-induced functional changes in a cell-specific manner is unclear.

Methods: To address this gap in knowledge, we used the bilateral common carotid artery stenosis (BCAS) mouse model, and evaluated progressive functional changes to neurons, arterioles, astrocytes, and microglial cells at 14 and 28 days post-BCAS surgery. To assess the neuro-glio-vascular response to an acute ischemic insult, brain slices were superfused with low O₂ conditions. Using whole-cell patch-clamp electrophysiology, we measured basic membrane properties (e.g., resting membrane potential, capacitance, input resistance) in cortical pyramidal neurons. The activity of astrocytes was evaluated by monitoring Ca²⁺ from Aldh1l1-CreERT2; R26-lsl-GCaMP6f mice. Vascular reactivity to low O₂ from the BCAS mice was also assessed ex vivo.

Results: Our data showed no changes to the basic membrane properties of cortical pyramidal neurons. On the other hand, astrocyte activity was characterized by a progressive increase in the resting Ca²⁺. Notably, at 14 and 28 days post-BCAS, there was an increased expression of anti-inflammatory-related markers (IL-10, S100A10, TRPA1, and Nrf2). These data suggest that, in young mice, BCAS-induced increases in resting Ca²⁺ were associated with the expression of neuroprotective signals. Contrary to observations in glial cells, vascular function was impaired post-BCAS surgery, as shown by a blunted vasodilatory response to low O₂ and the vasodilatory signal, adenosine.

Conclusions: Together, these data suggest that, in young mice, BCAS leads to vascular dysfunction (e.g., impaired vasodilation in parenchymal arterioles), and in the absence of neuronal dysfunction, mild ischemia is associated with the activation of glial-derived neuroprotective signals.

Alzheimer's disease (AD) is the most common form of dementia with characteristic biological markers. Clinically, AD presents as declines in memory, reasoning, and decision making, but the loss of memory is particularly associated with hippocampal damage. Likewise, excessive ethanol consumption has been found to disrupt hippocampal function and integrity. To assess the potential shared consequences of AD pathology and ethanol, 5xFAD mice were administered 5 g/kg ethanol daily for 10 days. Immunohistochemical analysis revealed ethanol and AD converged to lead to microglial and astrocytic senescence as well as increased Aß-plaque formation in the hippocampus. Despite the exacerbation of these potential mechanisms of neurodegeneration, there were no additive effects of ethanol exposure and AD-related genotype on Fluoro-Jade C (FJC)+ cells or cognitive deficits in the novel object recognition task. Overall, these results are the first to characterize the effects of ethanol exposure on early adulthood in the 5xFAD mouse model. Together these findings support the idea that alcohol can influence AD pathology; however, the mechanisms involved in AD progression (e.g., glial activation and Aß-plaque) may be impacted prior to evidence of pathology (e.g., cognitive decline or neuronal loss).

The plasma membrane glucose transporter (GLUT)-2 is unique among GLUT family proteins in that it also functions as a glucose sensor. GLUT2 imposes sex-dimorphic control of hypothalamic astrocyte glucose storage and catabolism by unknown mechanisms. Mitogen-activated protein kinase (MAPK) signaling cascades operate within stress-sensitive signal transduction pathways. Current research employed an established primary astrocyte culture model and gene knockdown tools to investigate whether one or more of the three primary MAP kinase families are regulated by GLUT2. GLUT2 gene knockdown caused opposing adjustments in total ERK1/2 proteins in glucose-supplied male versus female astrocytes, augmenting or reducing the mean phosphorylated/total protein ratio for 44 and 42 kDa variants in these sexes. Glucose deprivation amplified this ratio for both ERK1/2 variants, albeit by a larger magnitude in male; GLUT2 siRNA exacerbated this stimulatory response in males only. Phosphorylated/total p38 MAPK protein ratios were up-regulated by GLUT2 knockdown in male, but not female astrocytes. Glucose-deprived astrocytes exhibited no change (male) or reduction (female) in this ratio after GLUT2 gene silencing. GLUT2 siRNA increased the phosphorylated/total protein ratio for 54 and 46 kDa SAPK/JNK proteins in each sex when glucose was present. However, glucose withdrawal suppressed (male) or amplified (female) these ratios, while GLUT2 knockdown attenuated these inverse responses. Results show that GLUT2 inhibits ERK1/2, p38, and SAPK/JNK MAPK activity in male, but differentially stimulates and inhibits activity of these signaling pathways in female hypothalamic astrocytes. Glucoprivation induces divergent adjustments in astrocyte p38 MAPK and SAPK/JNK activities. The findings demonstrate a stimulatory role for GLUT2 in p38 MAPK activation in glucose-starved female astrocytes, but can act as either an inhibitor or inducer of SAPK/JNK activation in glucose-deprived male versus female glial cells, respectively.