LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK.

BACKGROUND: LHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression. METHODS: In the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology. RESULTS: We found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPPflox/flox·CaMKIIαCre+ (conditional knockout) mice. Adeno-associated virus-mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIα and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation-induced depression-like behaviors. CONCLUSIONS: These findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder.

Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease.

Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

HnRNPK is involved in stress-induced depression-like behavior via ERK-BDNF pathway in mice.

As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.

ApoE4 exacerbates the senescence of hippocampal neurons and spatial cognitive impairment by downregulating acetyl-CoA level.

Although aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late-onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4- and ApoE3- target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome-lysosome-autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age-dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac-CoA); GTA supplement, an Ac-CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre-/post-synaptic plasticity-related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl-CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers.

ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease.

BACKGROUND: Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. METHODS: We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice. RESULTS: We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner. CONCLUSION: ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

p38 and ERK1/2-Dependent Activation of c-Jun Is Required for the Downregulation of Oxidative Stress-Induced ERα in Hypothalamic Astrocytes.

INTRODUCTION: Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that plays important roles in the female fertility. Accumulating evidence suggests that ERα present in the astrocytes of the hypothalamus region is essential for production of GnRH. The astrocytes display age-related senescence associated to oxidative stress induced by the estrogen metabolites. However, it is still unclear whether and how ERα expression changes during astrocyte aging. METHODS: Immunofluorescence was performed to analyze the ERα gene levels in hypothalamic astrocytes of naturally aging C57BL/6J female mice. We employed an oxidative stress cell model receiving 2-hydroxyestradiol (2OH-E2) intervention to confirm the downregulation of ERα expression in primary astrocytes. Western blot analysis was used to explore which oxidative stress signaling pathways induced loss of the ERα gene. Finally, ChIP-qPCR was employed to evaluate whether the c-Jun protein is able to regulate ERα gene expression. RESULTS: Compared to young mice, we found that the ERα expression of mid-aged mice was significantly decreased. In hypothalamic astrocytes, 2OH-E2 treatment significantly reduced the expression of the ERα gene. Moreover, we observed that transcription factor c-Jun could directly inhibit transcriptional ERα gene expression and might also reduce it by decreasing H3K27 acetylation at promoter regions. Administration of the antioxidants Rg1 and astaxanthin significantly attenuated the decrease in ERα gene expression induced by oxidative stress. CONCLUSIONS: The current data demonstrate that oxidative stress leads to loss of ERα involving the activation of the p38 and ERK1/2 pathways and the induction of the c-Jun protein in hypothalamic astrocytes. C-Jun protein regulates ERα gene expression via direct transcriptional repression or involving histone acetylation modifications at ERα gene promoter sites.

Circuit-wide proteomics profiling reveals brain region-specific protein signatures in the male WKY rats with endogenous depression.

BACKGROUND: Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined. METHODS: Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment-based clustering analysis, Venn diagram analysis, and Pearson correlation analysis. RESULTS: The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079. LIMITATIONS: Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation. CONCLUSION: The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

A Moderate Duration of Stress Promotes Behavioral Adaptation and Spatial Memory in Young C57BL/6J Mice.

Stress may serve multiple roles in cerebral functioning, ranging from a highly appropriate behavioral adaptation to a critical risk factor for susceptibility to mood disorder and cognitive impairment. It is well known that E/I (excitation/inhibition) balance is essential for maintaining brain homeostasis. However, it remains largely unknown how GABAergic and Glutamatergic neurons respond to different stressful stimuli and whether the GABAergic-Glutamatergic neuron balance is related to the transition between adaptive and maladaptive behaviors. Here, we subjected 3-month-old mice to chronic mild stress (CMS) for a period of one, two, and four weeks, respectively. The results showed that the two-week CMS procedure produced adaptive effects on behaviors and cognitive performance, with a higher number of GABAergic neuron and VGluT1-positive neurons, increasing the expressions of p-GluN2B, Reelin, and syn-PSD-95 protein in the hippocampus. In contrast, the prolonged behavioral challenge (4 week) imposes a passive coping behavioral strategy and cognitive impairment, decreased the number of GABAergic neuron, hyperactivity of VGluT1-positive neuron, increased the ratio of p-GluN2B, and decreased the expression of Reelin, syn-PSD-95 in the hippocampus. These findings suggest that a moderate duration of stress probably promotes behavioral adaptation and spatial memory by maintaining a GABAergic-Glutamatergic neuron balance and promoting the expression of synaptic plasticity-related proteins in the brain.

Ganoderma Lucidum Triterpenoids Improve Maternal Separation-Induced Anxiety- and Depression-like Behaviors in Mice by Mitigating Inflammation in the Periphery and Brain.

Although early life stress (ELS) can increase susceptibility to adulthood psychiatric disorders and produce a greater inflammatory response in a stressful event, targeted preventive and therapeutic drugs still remain scarce. Ganoderma lucidum triterpenoids (GLTs) can exert anti-inflammatory effects in the periphery and central nervous systems. This study employed a combined model of "childhood maternal separation + adulthood sub-stress" to explore whether GLTs may alleviate anxiety- and depression-like behaviors in male and female mice by mitigating inflammation. Male and female pups were separated from their mothers for four hours per day from postnatal day 1 (PND 1) to PND 21; starting from PND 56, GLTs were administered intraperitoneally once daily for three weeks and followed by three days of sub-stress. Results showed that maternal separation increased the anxiety- and depression-like behaviors in both male and female mice, which disappeared after the preemptive GLTs treatment (40 mg/kg) before adulthood sub-stress. Maternal separation up-regulated the pro-inflammatory markers in the periphery and brain, and activated microglia in the prefrontal cortex and hippocampus. All the abnormalities were reversed by GLTs administration, with no adverse effects on immune organ indices, liver, and renal function. Our findings suggest that GLTs can be a promising candidate in treating ELS-induced psychiatric disorders.

Metformin alleviates the depression-like behaviors of elderly apoE4 mice via improving glucose metabolism and mitochondrial biogenesis.

Apolipoprotein E4 (apoE4) is closely related to late-onset depression (LOD). In addition, the benefits of metformin treatment of depression have been documented in a range of rodent studies and human trials, but few studies have probed into the effect of metformin on and the related mechanism in depressed elderly mice, especially in those APOE4 carriers. Here, we treated 13-month-old apoE3-targeted replacement (TR) and apoE4-TR mice with an intragastric administration of metformin (300 mg/kg/d) or normal saline for 5 months. We found that metformin exerted antidepressant effects on apoE4 mice, including reduced immobility time in TST and FST, and increased ratios of time and distance in the central area of OFT. Importantly, compared with apoE3 mice, apoE4 mice showed a higher expression of lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK1 and PDK4) in the hippocampus. The increased LDH level was rescued by metformin treatment. Moreover, the metformin administration increased the levels of transcriptional factor NRF-1 and TFAM, mtDNA, and most mitochondrial complex subunits in apoE-TR mice. Furthermore, it upregulated the expressions of antioxidant enzymes, such as MnSOD, GPX1, and GSR1/2. Interestingly, apoE4 blunted the hypoglycemic effect of metformin in aged mice. These data suggest that metformin ameliorates the depression-like behaviors probably by improving glucose metabolism and mitochondria biogenesis in the hippocampus of aged apoE4 mice. These findings imply that chronic metformin treatment can improve apoE4-mediated LOD, providing mechanistic insights for apoE4- and age-based depression prevention and therapy.

APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline.

Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

ApoE4 increases susceptibility to stress-induced age-dependent depression-like behavior and cognitive impairment.

Though apolipoprotein E ε4 (APOE ε4) is a major genetic risk factor for late-onset Alzheimer's disease, its association with depression remains controversial. In present study, 3-month-old and 8-month-old apoE-targeted replacement (TR) mice were both subjected to chronic unpredictable mild stress (CUMS) for six weeks. The results showed that 8-month apoE4-TR mice were more susceptible to the CUMS-induced depression-like behaviors and cognitive impairment than age-matched apoE3-TR mice. Stress induced a loss of GABAergic neurons and decline of Reelin level in the prefrontal cortex (PFC) and in the dentate gyrus (DG) of the hippocampus in both 3-month-old and 8-month-old apoE-TR mice, which were more pronounced in the 8-month-old apoE4-TR mice. Of note, stress decreased the level of PSD95 in the hippocampal synaptosome and increased the phosphorylation of N-methyl-D-aspartate receptor subunit GluN2B in the hippocampus of 8-month-old apoE4-TR mice. However, the expressions of apoE and apoE receptor 2 (apoER2) were not affected by stress. The study provides rodent evidence that APOE ε4 may increase the risk of depression and dementia in the elderly population by impairing the GABAergic signaling pathway and enhancing the GluN2B phosphorylation, which signifies that GluN2B inhibitors in clinical settings may be effective for elderly depression patients with APOE4 carriers.

Increased Notch2/NF-κB Signaling May Mediate the Depression Susceptibility: Evidence from Chronic Social Defeat Stress Mice and WKY Rats.

The susceptibility to depression has been attributed to the chronic stress and genetic factors but still fails to identify definite biomarkers. The present study aimed to investigate the role of disrupted Notch signaling in the medial prefrontal cortex of the chronic social defeat stress (CSDS) mice and Wistar Kyoto (WKY) rats. RNA-sequencing and quantitative real-time PCR analyses evidenced the involvement of Notch signaling pathway in depression. Western blotting reported an increased level of Notch2 and NF-κB and a decreased level of Hes1 and Bcl2/Bax ratio both in the susceptible mice when compared with the control or resilient ones and in the depression WKY rats when compared with the Wistar or non-depression WKY groups. Further analysis showed that the above-mentioned changes were significantly correlated with the depression-like behaviors and that the elicited Notch2 strongly correlated with the upregulated NF-κB, not with the downregulated Hes1 or Bcl2/Bax ratio. In conclusion, the increased Notch2/NF-κB signaling in the medial prefrontal cortex may mediate depression susceptibility, providing a potential diagnostic biomarker or therapeutic target for treating major depressive disorder.

Acetate supplementation produces antidepressant-like effect via enhanced histone acetylation.

BACKGROUND: Abnormal energy metabolism is often documented in the brain of patients and rodents with depression. In metabolic stress, acetate serves as an important source of acetyl coenzyme A (Ac-CoA). However, its exact role and underlying mechanism remain to be investigated. METHOD: We used chronic social failure stress (CSDS) to induce depression-like phenotype of C57BL/6J mice. The drugs were administered by gavage. We evaluated the depressive symptoms by sucrose preference test, social interaction, tail suspension test and forced swimming test. The dendritic branches and spine density were detected by Golgi staining, mRNA level was analyzed by real-time quantitative RT-PCR, protein expression level was detected by western blot, and the content of Ac-CoA was detected by ELISA kit. RESULT: The present study found that acetate supplementation significantly improved the depression-like behaviors of mice either in acute forced swimming test (FST) or in CSDS model and that acetate administration enhanced the dendritic branches and spine density of the CA1 pyramidal neurons. Moreover, the down-regulated levels of BDNF and TrkB were rescued in the acetate-treated mice. Of note, chronic acetate treatment obviously lowered the transcription level of HDAC2, HDAC5, HDAC7, HDAC8, increased the transcription level of HAT and P300, and boosted the content of Ac-CoA in the nucleus, which facilitated the acetylation levels of histone H3 and H4. LIMITATIONS: The effect of acetate supplementation on other brain regions is not further elucidated. CONCLUSION: These findings indicate that acetate supplementation can produce antidepressant-like effects by increasing histone acetylation and improving synaptic plasticity in hippocampus.

SIK2 represses AKT/GSK3ß/ß-catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases.

Salt-inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial-mesenchymal transition via inhibition of AKT/GSK3ß/ß-catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3ß/ß-catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice.

Hypothalamic astrocytes are important contributors that activate gonadotropin-releasing hormone (GnRH) neurons and promote GnRH/LH (luteinizing hormone) surge. However, the potential roles and mechanisms of astrocytes during the early reproductive decline remain obscure. The current study reported that, in intact middle-aged female mice, astrocytes within the hypothalamic RP3V accumulated senescence-related markers with increasing age. It employed an ovariectomized animal model and a cell model receiving estrogen intervention to confirm the estrogen-induced senescence of hypothalamic astrocytes. It found that estrogen metabolites may be an important factor for the estrogen-induced astrocyte senescence. In vitro molecular analysis revealed that ovarian estradiol activated PKA and up-regulated CYPs expression, metabolizing estradiol into 2-OHE2 and 4-OHE2. Of note, in middle-aged mice, the progesterone synthesis and the ability to promote GnRH release were significantly reduced. Besides, the expression of growth factors decreased and the mRNA levels of proinflammatory cytokines significantly increased in the aging astrocytes. The findings confirm that ovarian estradiol induces the senescence of hypothalamic astrocytes and that the senescent astrocytes compromise the regulation of progesterone synthesis and GnRH secretion, which may contribute to the aging-related declines in female reproductive function.

Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation.

BACKGROUND: Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated. METHOD: C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg-1), SDS + FLUOX (3 mg kg-1), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons. RESULT: The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CA1 pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB). CONCLUSION: Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression.

Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner.

Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5-mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3-target replacement (TR) mice, not ApoE4-TR mice. It found that in aged ApoE3-TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4-TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3-TR and ApoE4-TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype-dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4- and age-related AD prevention and treatment.-Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner.