Senolytic treatment alleviates doxorubicin-induced chemobrain.

Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment.

Indole-3-carbinol ameliorated the thioacetamide-induced hepatic encephalopathy in rats.

Indole-3-carbinol (I3C) is reported to have hepatic and neuroprotective properties. However, the I3C role in the protection of the liver and brain in the pathological condition of hepatic encephalopathy has not been investigated. Therefore, in the present study, we have assessed the hepatic and neuroprotective roles of I3C against thioacetamide (TAA)- induced hepatic encephalopathy in Wistar rats. TAA (300 mg/kg) was intraperitoneally administered to Wistar rats to induce hepatic encephalopathy. The elevated levels of ammonia in the blood, liver, and brain were substantially lowered by I3C treatment (25, 50, and 100 mg/kg, oral, 7 days). I3C significantly ameliorated the TAA-induced liver dysfunction by decreasing the alanine transaminase, aspartate transaminase, and alkaline phosphatase enzymes and reduced the elevated cytochrome P4502E1 (CYP2E1) activity in the liver and brain. Further, I3C alleviated mitochondrial dysfunction and oxidative stress in the brain. I3C treatment improved the anti-inflammatory cytokine interleukin (IL)- 10 while reducing inflammatory cytokines such as tumor necrosis factor-1 and IL-6 in hepatic encephalopathy rats. I3C reduced the levels of apoptotic indicators mediated by the mitochondria, including cytochrome c, caspase 9, and caspase 3. Concurrently, I3C mitigated the liver and brain histological abnormalities in hepatic encephalopathy rats. Therefore, the present study concluded that the I3C protected the liver and brain from TAA-induced hepatic encephalopathy injury by inhibiting CYP2E1 enzyme activity and decreasing ammonia, oxidative stress, inflammation, and apoptosis. The present study provides preclinical validation of I3C use as hepatic and neuroprotective for hepatic encephalopathy management.

Enrichment of genomic pathways based on differential DNA methylation profiles associated with knee osteoarthritis pain.

Our study aimed to identify differentially methylated regions (i.e., genomic region where multiple adjacent CpG sites show differential methylation) and their enriched genomic pathways associated with knee osteoarthritis pain (KOA). We recruited cognitively healthy middle to older aged (age 45-85) adults with (n = 182) and without (n = 31) self-reported KOA pain. We also extracted DNA from peripheral blood that was analyzed using MethylationEPIC arrays. The R package minfi (Aryee et al., 2014) was used to perform methylation data preprocessing and quality control. To investigate biological pathways impacted by differential methylation, we performed pathway enrichment analysis using Ingenuity Pathway Analysis (IPA) to identify canonical pathways and upstream regulators. Annotated genes within ± 5 kb of the putative differentially methylated regions (DMRs, p < 0.05) were subjected to the IPA analysis. There was no significant difference in age, sex, study site between no pain and pain group (p > 0.05). Non-Hispanic black individuals were overrepresented in the pain group (p = 0.003). At raw p < 0.05 cutoff, we identified a total of 19,710 CpG probes, including 13,951 hypermethylated CpG probes, for which DNA methylation level was higher in the groups with highest pain grades. We also identified 5,759 hypomethylated CpG probes for which DNA methylation level was lower in the pain groups with higher pain grades. IPA revealed that pain-related DMRs were enriched across multiple pathways and upstream regulators. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e., antigen presentation, PD-1, PD-L1 cancer immunotherapy, B cell development, IL-4 signaling, Th1 and Th2 activation pathway, and phagosome maturation). Moreover, in terms of upstream regulators, NDUFAF3 was the most significant (p = 8.6E-04) upstream regulator. Our findings support previous preliminary work suggesting the importance of epigenetic regulation of the immune system in knee pain and the need for future work to understand the epigenetic contributions to chronic pain.

Interventional Challenges in Non-Tubal Ectopic Pregnancy.

Objective: Non-tubal ectopic pregnancies (EPs) are rare and potentially life threatening. The number is rising due to various risk factors and there are no uniform guidelines in the management of EPs. This study was done to assess risk factors and challenges in the management of EPs. Materials and methods: This is a retrospective observational descriptive study that was done at SDM College of Medical Sciences & Hospital, Shri Dharmasthala Manjunatheshwara University Dharwad, Karnataka India. Data was collected from the medical records section of all the patients of non-tubal ectopic pregnancies managed in our hospital from January 2020 to June 2021. The collected data were analyzed for demographic characteristics, risk factors and management. Results: The incidence of ectopic pregnancies in our institute was 6-7 per 1000 pregnancies, of which 20% of the ectopic pregnancies were non-tubal. The incidence was higher than the other studies, which could be due to our center being a tertiary care referral center. Cesarean scar ectopic pregnancies were the most common accounting for 60% of cases. The management varied from conservative to minimally invasive surgery to hysterectomy hysterectomy with bilateral internal iliac artery ligation, depending upon the clinical presentation, duration of gestation, presence of fetal cardiac activity and hemodynamic stability. The other non-tubal ectopic pregnancies were cervical, ovarian, corneal and heterotopic. Cervical pregnancy beyond 12 weeks of gestation was rare which was managed by conserving the uterus. Conclusion: Non-tubal ectopic pregnancies are rare. Early diagnosis requires a high index of suspicion if missed can lead to an array of complications leading to loss of fertility, morbidity, and mortality. The key step to avert the complications is early diagnosis and individualized treatment.

Examination of CA1 Hippocampal DNA Methylation as a Mechanism for Closing of Estrogen's Critical Window.

There is a critical window for estrogen replacement therapy, beyond which estradiol (E2) fails to enhance cognition and N-methyl-D-aspartate (NMDA) receptor function, and E2-responsive transcription decreases. Much less attention has been given to the mechanism for closing of the critical window, which is thought to involve the decline in estrogen signaling cascades, possibly involving epigenetic mechanisms, including DNA methylation. This study investigated changes in DNA methylation in region CA1 of the hippocampus of ovariectomized female rats over the course of brain aging and in response to E2-treatment, using whole genome bisulfite sequencing. Differential methylation of CpG and non-CpG (CHG and CHH) sites and associated genes were characterized in aged controls (AC), middle-age controls (MC), and young controls (YC) and differential methylation in response to E2-treatment (T) was examined in each age group (AT-AC, MT-MC, and YT-YC). Possible candidate genes for the closing of the critical window were defined as those that were hypomethylated by E2-treatment in younger animals, but were unresponsive in aged animals. Gene ontology categories for possible critical window genes were linked to response to hormones (Adcyap1, Agtr2, Apob, Ahr, Andpro, Calm2, Cyp4a2, Htr1b, Nr3c2, Pitx2, Pth, Pdk4, Slc2a2, Tnc, and Wnt5a), including G-protein receptor signaling (Gpr22 and Rgs4). Other possible critical window genes were linked to glutamate synapses (Nedd4, Grm1, Grm7, and Grin3a). These results suggest that decreased E2 signaling with advanced age, and/or prolonged E2 deprivation, results in methylation of E2-responsive genes, including those involved in rapid E2 signaling, which may limit subsequent transcription.

Prediagnostic White Blood Cell DNA Methylation and Risk of Breast Cancer in the Prostate Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort.

BACKGROUND: White blood cell (WBC) DNA may contain methylation patterns that are associated with subsequent breast cancer risk. Using a high-throughput array and samples collected, on average, 1.3 years prior to diagnosis, a case-cohort analysis nested in the prospective Sister Study identified 250 individual CpG sites that were differentially methylated between breast cancer cases and noncases. We examined five of the top 40 CpG sites in a case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort. METHODS: We investigated the associations between prediagnostic WBC DNA methylation in 297 breast cancer cases and 297 frequency-matched controls. Two WBC DNA specimens from each participant were used: a proximate sample collected 1 to 2.9 years and a distant sample collected 4.2-7.3 years prior to diagnosis in cases or the comparable timepoints in controls. WBC DNA methylation level was measured using targeted bisulfite amplification sequencing. We used logistic regression to obtain ORs and 95% confidence intervals (CI). RESULTS: A one-unit increase in percent methylation in ERCC1 in proximate WBC DNA was associated with increased breast cancer risk (adjusted OR = 1.29; 95% CI, 1.06-1.57). However, a one-unit increase in percent methylation in ERCC1 in distant WBC DNA was inversely associated with breast cancer risk (adjusted OR = 0.83; 95% CI, 0.69-0.98). None of the other ORs met the threshold for statistical significance. CONCLUSIONS: There was no convincing pattern between percent methylation in the five CpG sites and breast cancer risk. IMPACT: The link between prediagnostic WBC DNA methylation marks and breast cancer, if any, is poorly understood.

Optimum multi-drug regime for compartment model of tumour: cell-cycle-specific dynamics in the presence of resistance.

This work is focused on multi-objective optimisation of a multi-drug chemotherapy schedule for cell-cycle-specific cancer treatment under the influence of drug resistance. The acquired drug resistance to chemotherapeutic agents is incorporated into the existing compartmental model of breast cancer. Furthermore, the toxic effect of drugs on healthy cells and overall drug concentration in the patient body are also constrained in the proposed model. The objective is to determine the optimal drug schedule according to the patient's physiological condition so that the tumour burden is minimised. A multi-objective optimisation algorithm, non-dominated sorting genetic algorithm-II (NSGA-II) is utilised to solve the problem. The obtained results are thoroughly analysed to illustrate the impact of drug resistance on the treatment. The capability of optimised schedules to deal with parametric uncertainty is also analysed. The drug schedules obtained in this work align well with the clinical standards. It is also revealed that the NSGA-II optimised drug schedule with proper rest period between successive dosages yields the minimum cancer load at the end of the treatment.

Enrichment of genomic pathways based on differential DNA methylation profiles associated with chronic musculoskeletal pain in older adults: An exploratory study.

Our study aimed to identify differentially methylated CpGs/regions and their enriched genomic pathways associated with underlying chronic musculoskeletal pain in older individuals. We recruited cognitively healthy older adults with (n = 20) and without (n = 9) self-reported musculoskeletal pain and collected DNA from peripheral blood that was analyzed using MethylationEPIC arrays. We identified 31,739 hypermethylated CpG and 10,811 hypomethylated CpG probes (ps ≤ 0.05). All CpG probes were clustered into 5966 regions, among which 600 regions were differentially methylated at p ≤ 0.05 level, including 294 hypermethylated regions and 306 hypomethylated regions (differentially methylated regions). Ingenuity pathway enrichment analysis revealed that the pain-related differentially methylated regions were enriched across multiple pathways. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e. antigen presentation, programed cell death 1 receptor/PD-1 ligand 1, interleukin-4, OX40 signaling, T cell exhaustion, and apoptosis) and gamma-aminobutyric acid receptor signaling. Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.

Pediatric lung transplantation: Dynamics of the microbiome and bronchiolitis obliterans in cystic fibrosis.

BACKGROUND: Compositional changes in the microbiome are associated with the development of bronchiolitis obliterans (BO) after lung transplantation (LTx) in adults with cystic fibrosis (CF). The association between the lower airway bacterial community and BO after LTx in children with CF remains largely unexplored and is possibly influenced by frequent antibiotic therapy. The objectives of this study were to examine the relationship between bacterial community dynamics and the development of BO and analyze antibiotic resistance trends in children after LTx for CF. METHODS: For 3 years from the time of transplant, 12 LTx recipients were followed longitudinally, with 5 subjects developing BO during the study period. A total of 82 longitudinal bronchoalveolar lavage samples were collected during standard of care bronchoscopies. Metagenomic shotgun sequencing was performed on the extracted microbial DNA from bronchoalveolar lavage specimens. Taxonomic profiling was constructed using WEVOTE pipeline. The longitudinal association between development of BO and temporal changes in bacterial diversity and abundance were evaluated with MetaLonDA. The analysis of antibiotic resistance genes was performed with the ARGs-OAP v2.0 pipeline. RESULTS: All recipients demonstrated a Proteobacteria-predominant lower airways community. Temporal reduction in bacterial diversity was significantly associated with the development of BO and associated with neutrophilia and antibiotic therapy. Conversely, an increasing abundance of the phylum Actinobacteria and the orders Neisseriales and Pseudonocardiales in the lower airways was significantly associated with resilience to BO. A more diverse bacterial community was related to a higher expression of multidrug resistance genes and increased proteobacterial abundance. CONCLUSIONS: Decreased diversity within bacterial communities may suggest a contribution to pediatric lung allograft rejection in CF.

Abundance of Multidrug Resistance Efflux Pumps in the Urinary Metagenome of Kidney Transplant Patients.

Antibiotic resistance including the emergence of multidrug resistant microbes has become a public health crisis. In this study, we analyzed the antibiotic resistance genes (ARGs) in the urinary metagenome of the kidney transplant and healthy subjects using metagenomic shotgun sequencing. Our data suggest an increased abundance of antibiotic resistance genes in the kidney transplant subjects. In addition, the antibiotic resistance genes identified in the transplant subjects were predominantly composed of multidrug efflux pumps (MDEPs) which are evolutionarily ancient, commonly encoded on chromosomes rather than plasmids, and have a low rate of mutation. Since the MDEPs had a low abundance in the healthy subjects, we speculate that the MDEPs may enhance the fitness of bacteria to survive in the high stress environment of transplantation that includes multiple stressors including surgery, antibiotics, and immunosuppressive agents.

Reliable anatase-titania nanoclusters functionalized GaN sensor devices for UV assisted NO2 gas-sensing in ppb level.

Internet of Things applications require ultra-low power, integrable into electronic circuits and mini-sized chemical sensors for automated remote air quality monitoring system. In this work, a highly sensitive and selective detection of nitrogen dioxide (NO2) has been demonstrated by functionalizing gallium nitride (GaN) submicron wire with titania (TiO2) nanoclusters. The two-terminal GaN/TiO2 sensor device was fabricated by top-down approach. The photo-enabled sensing makes it possible to operate this sensor at room-temperature, resulting in a significant reduction in operating power. The GaN/TiO2 sensor was able to detect NO2 concentrations as low as 10 ppb in air at room temperature (20 °C) with a quick response-recovery process. The sensor was found highly selective toward NO2 against other interfering gases, such as ethanol (C2H5OH), ammonia (NH3), sulfur dioxide (SO2), methane (CH4) and carbon dioxide (CO2). Furthermore, principal component analysis has been performed to address the cross-sensitive nature of TiO2. The sensor device exhibited excellent long-term stability at room temperature and humidity and was quite stable and reliable at various environmental conditions. Continuous exposure of the device to siloxane for a one-month period has shown a very small degradation in sensor response to NO2. Finally, interaction of NO2 gas molecules with the GaN/TiO2 sensor has been modeled and explained under the light of energy band diagram. The photoinduced oxygen desorption and subsequent charge transfer between TiO2 nanoclusters and NO2 molecules modulate the depletion region width within the GaN, thus contributing to a high performance NO2 gas sensing.

Tuning the Polarity of MoTe2 FETs by Varying the Channel Thickness for Gas-Sensing Applications.

In this study, electrical characteristics of MoTe2 field-effect transistors (FETs) are investigated as a function of channel thickness. The conductivity type in FETs, fabricated from exfoliated MoTe2 crystals, switched from p-type to ambipolar to n-type conduction with increasing MoTe2 channel thickness from 10.6 nm to 56.7 nm. This change in flake-thickness-dependent conducting behavior of MoTe2 FETs can be attributed to modulation of the Schottky barrier height and related bandgap alignment. Change in polarity as a function of channel thickness variation is also used for ammonia (NH3) sensing, which confirms the p- and n-type behavior of MoTe2 devices.

Modified fractional order IMC design based drug scheduling for cancer treatment.

This paper aims to improve chemotherapy drug(s) scheduling of the drug dose injected into a patient. The existing practice has been established on experiments performed during the drug development process. In general, chemotherapeutic drugs are highly toxic in nature and directly affect the probability of a patient's survival. Therefore, a modified fractional order internal model control (MFOIMC) scheme with a minimal number of design parameters is proposed for effective drug scheduling. The proposed control scheme is a combination of fractional calculus and IMC. The fractional order IMC (FOIMC) is modified by incorporating an extra control loop with a proportional transfer function. Further, IPD and IMC control techniques are also designed for comparative analysis. The dragon fly algorithm (DA) is employed to optimize the parameters of the controller. Results show that the proposed control scheme provides a continuous and precise chemotherapeutic drug dose to the patient on a daily basis. It is also shown that MFOIMC improves IAE by 34% and 32% in comparison to IMC and FOIMC, respectively, which proves its superiority over other controllers.

Complete Genome Sequence of BK Polyomavirus Subtype Ib-1 Detected in a Kidney Transplant Patient with BK Viremia Using Shotgun Sequencing.

We report here the complete genome sequence of polyomavirus BK subtype Ib-1, isolate AR11, identified in urine from a human kidney transplant recipient with a clinical diagnosis of BK viremia. The AR11 isolate is closely related to reference strain human polyomavirus 1 isolate J2B-2 with 99% identity.

α-Chymotrypsin regulates free fatty acids and UCHL-1 to ameliorate N-methyl nitrosourea induced mammary gland carcinoma in albino wistar rats.

This study was undertaken to investigate the effect of α-chymotrypsin on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized into four groups (six animals in each). Group I (sham control 0.9 % normal saline p.o.); Group II (toxic control, MNU 47 mg/kg, i.v.); Group III (α-chymotrypsin, 5 mg/kg, p.o.); Group IV (α-chymotrypsin, 10 mg/kg p.o.). Toxicity was induced by single i.v. injection of MNU followed by α-chymotrypsin supplementation therapy for 100 days. MNU treatment was evident with increased alveolar bud count, differentiation score, upregulated inflammatory enzymes markers (COX, LOX and NO) antioxidative stress markers (TBARs, SOD, catalase and GSH).MNU associated toxicity was also ascertained by PGP 9.5 and NF-κB expression in the mammary gland tissue followed by FAME analysis for fatty acid profiling. α-chymotrypsin afforded significant protection against the deleterious effects of MNU.

A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms.

Recent studies have established that the human urine contains a complex microbiome, including a virome about which little is known. Following immunosuppression in kidney transplant patients, BK polyomavirus (BKV) has been shown to induce nephropathy (BKVN), decreasing graft survival. In this study we investigated the urine virome profile of BKV+ and BKV- kidney transplant recipients. Virus-like particles were stained to confirm the presence of VLP in the urine samples. Metagenomic DNA was purified, and the virome profile was analyzed using metagenomic shotgun sequencing. While the BK virus was predominant in the BKV+ group, it was also found in the BKV- group patients. Additional viruses were also detected in all patients, notably including JC virus (JCV) and Torque teno virus (TTV) and interestingly, we detected multiple subtypes of the BKV, JCV and TTV. Analysis of the BKV subtypes showed that nucleotide polymorphisms were detected in the VP1, VP2 and Large T Antigen proteins, suggesting potential functional effects for enhanced pathogenicity. Our results demonstrate a complex urinary virome in kidney transplant patients with multiple viruses with several distinct subtypes warranting further analysis of virus subtypes in immunosuppressed hosts.

Radon levels in drinking water and soil samples of Jodhpur and Nagaur districts of Rajasthan, India.

Radon causes lung cancer when it is trapped inside the lungs. Therefore it is very important to analyze the radon concentration in water and soil samples. In the present investigation, water and soil samples collected from 20 different locations of Jodhpur and Nagaur districts of Northern Rajasthan, India have been studied by using RAD7. The measured radon concentration in water samples varies from 0.5 to 15Bql(-1). The observed values lie within the safe limit as set by UNSCEAR, 2008. The total annual effective dose due to radon in water corresponding to all studied locations has been found to be well within the safe limit of 0.1mSvy(-1) as recommended by World Health Organization (WHO, 2004) and European Council (EU, 1998). The measurements carried out on radon concentration in soil samples reveal a variation from 1750 to 9850Bqm(-3). These results explore that the water of Jodhpur and Nagaur districts is suitable for drinking purpose without posing any health hazard but soil hazards depend upon its permeability and radon concentration.

ASSESSMENT OF AGE-DEPENDENT RADIATION DOSE DUE TO INTAKE OF URANIUM AND THORIUM IN DRINKING WATER FROM SIKAR DISTRICT, RAJASTHAN, INDIA.

The concentrations of 238U and 232Th have been determined in drinking water samples collected from the Sikar district of Rajasthan State, India. The samples have been analysed by using high-resolution inductively coupled plasma mass spectrometry. 238U content in water samples ranged from 8.20 to 202.63 µg l-1 and 232Th content ranged from 0.57 to 1.46 µg l-1 The measured 238U content in 25 % of the analysed samples exceeded the World Health Organization (WHO) and United States Environmental Protection Agency drinking water guidelines of 30 µg l-1 and 12.5 % of the samples exceeded the 60 µg l-1 Indian maximum acceptable concentration recommended by the Atomic Energy Regulatory Board, India. The annual effective doses (µSv y-1) due to ingestion of 238U and 232Th for different age groups were also calculated. The results compared with the recommended value reported by the WHO.

Re-Opening the Critical Window for Estrogen Therapy.

A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor α (ERα) or estrogen receptor ß (ERß) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ERα, ERß, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17ß-estradiol-3-benzoate (EB, 10 µg) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ERß (ERß + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ERß failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα + EB), such that memory was improved relative to ERα + oil and GFP + EB. Similarly, ERα + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ERα + oil and GFP + EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ERα. SIGNIFICANCE STATEMENT: Estradiol is neuroprotective, promotes synaptic plasticity in the hippocampus, and protects against cognitive decline associated with aging and neurodegenerative diseases. However, animal models and clinical studies indicate a critical window for the therapeutic treatment such that the beneficial effects are lost with advanced age and/or with extended hormone deprivation. We used gene therapy to upregulate expression of the estrogen receptors ERα and ERß and demonstrate that the window for estradiol's beneficial effects on memory and hippocampal synaptic function can be reinstated by enhancing the expression of ERα. Our findings suggest that the activity of ERα controls the therapeutic window by regulating synaptic plasticity mechanisms involved in memory.

Contribution of estrogen receptor subtypes, ERα, ERß, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice.

Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. This study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3-5-month-old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERßKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10-16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts before and following application of 17ß-estradiol-3-benzoate (EB, 100 pM), the G-protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERß selective agonist diarylpropionitrile (DPN, 1 µM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB-mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERß selective agonists (PPT and DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal-regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes.