Sex Specificity Research Articles

The inflammatory state provokes sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats

Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus.

VviAPRT3 and VviFSEX: Two Genes Involved in Sex Specification Able to Distinguish Different Flower Types in Vitis.

Vitis vinifera vinifera is a hermaphrodite subspecies, while its ancestor, Vitis vinifera sylvestris, is dioecious. We have identified two genes that together allow the discrimination between male, female and hermaphrodite Vitis plants. The sex locus region on chromosome 2 was screened resulting in the discovery of a new gene, VviFSEX. The same screening revealed another gene, VviAPRT3, located in the sex region, that be used as a sex marker. Both genes are good candidates to be involved in flower sex differentiation in grapevine. To assess their role in sex specification, spatial and temporal expression analysis was performed. The expression of VviFSEX is detected in petals, stamens and carpel primordia of all flower types, making its putative function unclear; however, female plants display a single allele for this gene, while male and hermaphrodites display two alleles. On the other hand, the specific expression of VviAPRT3 in the carpel primordial of male plants suggests a possible role in the abortion of pistil structures. We propose a model to explain the carpel abortion in male flowers and the absence of stamen viability in female flowers. In addition, this work reinforces the presence of a sex locus on Vitis chromosome 2.

Sexually Dimorphic Differentiation of a C. elegans Hub Neuron Is Cell Autonomously Controlled by a Conserved Transcription Factor

Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neuron pair of the nematode C.elegans differentiates in a strikingly sex-specific manner. In hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, but in males PHC differentiates into a densely connected hub sensory neuron/interneuron, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We show that the differentiation into such a hub neuron involves thesex-specific scaling of several components of thesynaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology, and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured byitscollaboration with non-sex-specific terminal selector-type transcription factors, whereas the sex specificity of dmd-3 action is ensured by the hermaphrodite-specific transcriptional master regulator of hermaphroditic cell identity tra-1, which represses the transcription of dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner.

Психологические особенности мотивации и ценностей у старшеклассников разного пола

This research focuses on sex-specific differences in motivational, meaning- and value-based attitudes to learning in high school students. The sample included students of 9-11 grades (aged 15-17 years) of two Moscow schools with traditional paradigm in education. Motivational attitudes were measured with factor analysis of the subjects’ responses to 70 statements (different sets for male and female groups; the total number of respondents was 162, 82 males and 80 females). The structure of value orientations was studied with cluster analysis of ranking of 10 terminal human values (Rokeach) and 12 learning values (109 respondents, 60 females and 49 males). The correlation between the character of motivation and value orientations was also explored in the study (39 males and 48 females were presented with both surveys). The outcomes of the study show that young girls find opportunities for self-actualisation in knowledge and experience, in personal growth and overcoming difficulties in life, whereas young boys mostly associate self-actualisation with affiliative sphere. The character of motivation in young girls clearly corresponds with the values they choose, while in boys the relationship between motivations and values seems ambiguous. Taking into account sex specifics in adolescents may help raise the effectiveness of learning activity

Sex-Dependent Role of Estrogen Sulfotransferase and Steroid Sulfatase in Metabolic Homeostasis.

Sulfonation and desulfation are two opposing processes that represent an important layer of regulation of estrogenic activity via ligand supplies. Enzymatic activities of families of enzymes, known as sulfotransferases and sulfatases, lead to structural and functional changes of the steroids, thyroids, xenobiotics, and neurotransmitters. Estrogen sulfotransferase (EST) and steroid sulfatase (STS) represent negative and positive regulation of the estrogen activity, respectively. This is because EST-mediated sulfation deactivates estrogens, whereas STS-mediated desulfation converts the inactive estrogen sulfates to active estrogens. In addition to the known functions of estrogens, EST and STS in reproductive processes, regulation of estrogens and other signal molecules especially at the local tissue levels has gained increased attention in the context of metabolic disease in recent years. EST expression is detectable in the subcutaneous adipose tissue in both obese women and men, and the expression of EST is markedly induced in the livers of rodent models of obesity and type 2 diabetes. STS was found to be upregulated in patients with chronic inflammatory liver diseases. Interestingly, the tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity. EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Adipogenesis is also differentially regulated by EST in murine and human adipocytes. This chapter focuses on the recent progress in our understanding of the expression and regulation EST and STS in the context of metabolic homeostasis.

Sub foveal choroidal thickness by enhanced depth imaging optical coherence tomography in type II diabetes mellitus

Objectives To evaluate the subfoveal choroidal thickness (ChT) in type II diabetes mellitus (DM) using enhanced depth imaging optical coherence tomography (EDI-OCT). Background Diabetic retinopathy (DR) is because of hemodynamic abnormalities. The choroid provides oxygen and nutrients to the outer retina. EDI-OCT can image the choroid in vivo. Patients and methods A prospective clinical randomized study was carried out focusing on 100 eyes of 100 patients divided into two groups: group A included 50 eyes of 50 diabetic patients with type II DM (20–50 years) and group B included 50 eyes of 50 age-matched normal healthy controls with no sex or laterality specification. The subfoveal ChT, using EDI-OCT, was measured from the posterior edge of retinal pigment epithelium to the choroioscleral junction. Results The mean age of the patients was 42 ± 7 and 39 ± 9 years in group A and B, respectively. The mean DM duration in group A was 7.96 ± 3.9 years. Subfoveal ChT was found to be 291 ± 42 μm in group A [275.31 ± 31 μm for no apparent retinopathy (no DR), 298 ± 42 μm for nonproliferative diabetic retinopathy, 309 ± 58 μm for proliferative diabetic retinopathy, 277 ± 29 μm for diabetic macular edema (DME) absent, and 306 ± 47 μm for DME present], whereas it was 284 ± 54 μm in group B. There was a statistically significant positive correlation between subfoveal ChT and DM duration (P = 0.00). Conclusion Subfoveal ChT was found to be correlated with the stage of DR. Progressive thickening of the choroid with the progression of DR and/or the development of DME may reflect the concurrent progression of diabetic choroidopathy.

Sex-Specific Neurodevelopmental Programming by Placental Insulin Receptors on Stress Reactivity and Sensorimotor Gating

BackgroundDiabetes, obesity, and overweight are prevalent pregnancy complications that predispose offspring to neurodevelopmental disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Although male individuals are three to four times more likely than female individuals to develop these disorders, the mechanisms driving the sex specificity of disease vulnerability remain unclear. Because defective placental insulin receptor (InsR) signaling is a hallmark of pregnancy metabolic dysfunction, we hypothesized that it may be an important contributor and novel mechanistic link to sex-specific neurodevelopmental changes underlying disease risk. MethodsWe used Cre/loxP transgenic mice to conditionally target InsRs in fetally derived placental trophoblasts. Adult offspring were evaluated for effects of placental trophoblast-specific InsR deficiency on stress sensitivity, cognitive function, sensorimotor gating, and prefrontal cortical transcriptional reprogramming. To evaluate molecular mechanisms driving sex-specific outcomes, we assessed genome-wide expression profiles in the placenta and fetal brain. ResultsMale, but not female, mice with placental trophoblast-specific InsR deficiency showed a significantly increased hypothalamic-pituitary-adrenal axis stress response and impaired sensorimotor gating, phenotypic effects that were associated with dysregulated nucleotide metabolic processes in the male prefrontal cortex. Within the placenta, InsR deficiency elicited changes in gene expression, predominantly in male mice, reflecting potential shifts in vasculature, amino acid transport, serotonin homeostasis, and mitochondrial function. These placental disruptions were associated with altered gene expression profiles in the male fetal brain and suggested delayed cortical development. ConclusionsTogether, these data demonstrate the novel role of placental InsRs in sex-specific neurodevelopment and reveal a potential mechanism for neurodevelopmental disorder risk in pregnancies complicated by maternal metabolic disorders, including diabetes and obesity.

Differential expression of foxl2 and cyp19a1a mRNA during gonad developmental stages in great sturgeon Huso huso.

This study aimed to determine the sex specificity and expression pattern of foxl2 and cyp19a1a genes in great sturgeon Huso huso gonads during gonadal sex differentiation and development. The results revealed that foxl2 and cyp19a1a mainly expressed in female gonads and during gonad development the foxl2 and cyp19a1a mRNA expression is required for ovarian development.

Association Between Sarcopenia and Cognitive Impairment: A Systematic Review and Meta-Analysis

BackgroundSarcopenia, a gradual loss of muscle mass and function, has been associated with poor health outcomes. Its correlation with another age-related degenerative process, impaired cognition, remains uncertain. This meta-analysis aimed to determine whether there is an association between sarcopenia and cognitive impairment. MethodsPubMed and Scopus were searched for observational studies that investigated the association between sarcopenia and cognitive dysfunction. Participants’ demographics and measurements, definition of sarcopenia, and tools for evaluating cognitive function were retrieved. The correlations between sarcopenia and cognitive impairment were expressed as crude and adjusted odds ratios with 95% confidence intervals (CIs). ResultsSeven cross-sectional studies comprising 5994 participants were included. The crude and adjusted odds ratios were 2.926 (95% CI, 2.297–3.728) and 2.246 (95% CI, 1.210–4.168), respectively. The subgroup analysis showed that different target populations and sex specificity did not significantly modify the association, whereas the tools for evaluating cognitive function and modalities for measuring body composition did. ConclusionsSarcopenia was independently associated with cognitive impairment. Future cohort studies are warranted to clarify the causal correlation. The inclusion of relevant biomarkers and functional measurements is also recommended to elucidate the underlying biological mechanism.

Deep analysis of wild Vitis flower transcriptome reveals unexplored genome regions associated with sex specification.

RNA-seq of Vitis during early stages of bud development, in male, female and hermaphrodite flowers, identified new loci outside of annotated gene models, suggesting their involvement in sex establishment. The molecular mechanisms responsible for flower sex specification remain unclear for most plant species. In the case of V. vinifera ssp. vinifera, it is not fully understood what determines hermaphroditism in the domesticated subspecies and male or female flowers in wild dioecious relatives (Vitis vinifera ssp. sylvestris). Here, we describe a de novo assembly of the transcriptome of three flower developmental stages from the three Vitis vinifera flower types. The validation of de novo assembly showed a correlation of 0.825. The main goals of this work were the identification of V. v. sylvestris exclusive transcripts and the characterization of differential gene expression during flower development. RNA from several flower developmental stages was used previously to generate Illumina sequence reads. Through a sequential de novo assembly strategy one comprehensive transcriptome comprising 95,516 non-redundant transcripts was assembled. From this dataset 81,064 transcripts were annotated to V. v. vinifera reference transcriptome and 11,084 were annotated against V. v. vinifera reference genome. Moreover, we found 3368 transcripts that could not be mapped to Vitis reference genome. From all the non-redundant transcripts that were assembled, bioinformatics analysis identified 133 specific of V. v. sylvestris and 516 transcripts differentially expressed among the three flower types. The detection of transcription from areas of the genome not currently annotated suggests active transcription of previously unannotated genomic loci during early stages of bud development.

Effects of oily fish intake on cardiovascular risk markers, cognitive function, and behavior in school-aged children: study protocol for a randomized controlled trial.

BackgroundMost children in Western populations do not meet recommendations for fish consumption. Oily fish is an important source of n-3 long-chain polyunsaturated fatty acids (LCPUFA), which reduce blood pressure and plasma triacylglycerol in adults and may affect cognitive development and behavior. However, to our knowledge, the potential effects of oily fish on cardiometabolic health, cognitive function, and behavior in children have not been investigated. The aim of the FiSK Junior study is to investigate the effects of oily fish consumption on cardiovascular risk markers, cognitive function, and behavior in healthy children.Methods/designWe are conducting a randomized controlled trial with 8- to 9-year-old Danish children, comparing the effect of consuming 300 g/week of oily fish with poultry (control) for 12 weeks between August 2016 and June 2017. The primary outcomes are blood pressure and fasting plasma triacylglycerol, which will be measured at baseline and endpoint. In addition, we will assess erythrocyte fatty acid composition (compliance), heart rate, plasma cholesterol, markers of glucose homeostasis, growth and body composition, dietary intake, and physical activity and sleep. We will also examine effects on cognitive function (attention, memory, and executive functions) by using standardized tests, behavior and emotions by administering parent-rated questionnaires and child interviews, and we will measure physiological stress response and cortisol levels. We need 150 children to complete the trial to detect a between-groups difference of 2.7 mmHg in diastolic blood pressure and 0.13 mmol/L in plasma triacylglycerol; thus, we aim to recruit 200 children. All outcomes will be analyzed in completer analysis supplemented with sensitivity analyses for the primary outcomes, and attention will be given to potential sex and genotype specificity.DiscussionThe results of the FiSK Junior study are expected to fill important gaps in the current knowledge about the importance of dietary fish and n-3 LCPUFA for children’s health and development, and may be used when setting dietary recommendations.Trial registrationClinicalTrials.gov identifier: NCT02809508. Registered on 22 June 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1647-z) contains supplementary material, which is available to authorized users.

Sex and Tissue Specificity of Peg3 Promoters.

The expression of mouse Peg3 (Paternally expressed gene 3) is driven by 4 promoters, including its main and three alternative promoters. The sexual, temporal and spatial specificity of these promoters was characterized in the current study. According to the results, the main promoter displays ubiquitous expression patterns throughout different stages and tissues. In contrast, the expression of Peg3 driven by the alternative promoter U2 was detected mainly in muscle and skin, but not in brain, starting from the late embryonic stage, revealing its tissue and stage specificity. The expression levels of both the main and U2 promoters are also sexually biased: the levels in females start higher but become lower than those in males during early postnatal stages. As an imprinted locus, the paternal alleles of these promoters are active whereas the maternal alleles are silent. Interestingly, deletion of the repressed maternal allele of the main promoter has an unusual effect on the opposite paternal allele, causing the up-regulation of both the main and U2 promoters. Overall, the promoters of Peg3 derive sexually biased and tissue-specific expression patterns.

Gender mismatches in partitive constructions with superlatives in French

This paper examines the syntax of partitive constructions with superlatives in French and the realization of gender in constructions with an animate noun, and focuses on contexts that allow gender mismatches (la plus intelligente de mes gentils professeurs ‘the most intelligent of my kind professors’). We show that such mismatches are allowed in French superlative partitives that contain a default masculine noun. To account for the mismatches, we propose that the nouns involved have an unvalued gender feature that can be assigned a sex specification in the course of the derivation. For superlative partitives we propose that this specification takes place in a Gender Phrase in the outer DP. Furthermore, we show that quantified partitives (e.g. three of the books) behave differently from superlative partitives, a fact we try to explain in terms of ­structural differences. We distinguish between partitives with an of-complement and ­non-canonical partitives with an ‘among’-PP or a preposed ‘of’-phrase. We also claim that our data can provide further insight into the role of locality in semantic agreement: we compare superlative partitives to quantified partitives in terms of agreement, and suggest that the two types of partitives should be placed in different positions on an Agreement Hierarchy.

Sex Difference in Condition Dependence of Carotenoid Gapes in the Eurasian Roller (Coracias garrulus).

In altricial birds, sex differentiation can start early in the ontogeny in the form of color, physiology, and/or growth and may potentially result in sex-specific condition dependence of traits mediating parent-offspring communication. Carotenoids have long been hypothesized to modulate the expression of gape coloration, but their sex-specific role enforcing honesty of gape coloration remains poorly studied. In a within-nest design, we provided carotenoid supplementation to nestlings of the Eurasian roller (Coracias garrulus) and measured the response in circulating carotenoids, coloration of the gape, cutaneous immune responsiveness to phytohemagglutinin, and growth while accounting for the sex of nestlings. Male nestlings supplemented with carotenoids displayed enhanced pigmentation of their gapes and grew faster than control nestlings, but there was no within-individual correlation between gape color and growth in either carotenoid-supplemented or control males. Female nestlings, however, diverted most supplemented carotenoids into growing fast at the expense of reducing their level of circulating carotenoids and displaying less-pigmented gapes. Nestling cutaneous immune response was not affected by carotenoid supplementation in either sex. Our results provide only weak support for the hypothesis that carotenoids enforce the honesty of gape color signals in nestling rollers and demonstrate sex specificity in how nestlings divert a surplus of carotenoids into different physiological functions.

Serum Cortisol: An Up-To-Date Assessment of Routine Assay Performance.

Accurate serum cortisol quantification is required for the correct diagnosis and management of adrenal pathologies. Presently, most laboratories use immunoassay to measure serum cortisol with proficiency schemes demonstrating a wide dispersion of results. Here, we investigate the effects of sex, matrix, and antibody specificity on serum cortisol quantification in 6 routine assays. Surplus serum was obtained before disposal and the following cohorts were created: males, nonpregnant females, pregnant patients, and patients prescribed either metyrapone or prednisolone. Samples were anonymized and distributed to collaborating laboratories for cortisol analysis by 6 routine assays. Cortisol was also measured in all samples using an LC-MS/MS candidate reference measurement procedure (cRMP); cortisol-binding globulin (CBG) was measured in the nonpregnant and pregnant female cohorts. Considerable inter- and intraassay variation was observed across the male and nonpregnant female cohorts relative to the cRMP. Four immunoassays underrecovered cortisol in the pregnancy cohort, and CBG was found to be significantly higher in this cohort than in the nonpregnant females. In the metyrapone and prednisolone cohorts, all immunoassays overestimated cortisol. The first generation Roche E170 and Siemens Centaur XP were particularly prone to overestimation. In all cohorts the routine LC-MS/MS assay aligned extremely well with the cRMP. Despite the clinical importance of serum cortisol, the performance of routine immunoassays remains highly variable. Accurate quantification is compromised by both matrix effects and antibody specificity. Underpinning this study with a cRMP has highlighted the deficiencies in standardization across routine cortisol immunoassays.

Genetic and Sex-Specific Transgenerational Effects of a High Fat Diet in Drosophila melanogaster.

An organism's phenotype is the product of its environment and genotype, but an ancestor’s environment can also be a contributing factor. The recent increase in caloric intake and decrease in physical activity of developed nations' populations is contributing to deteriorating health and making the study of the longer term impacts of a changing lifestyle a priority. The dietary habits of ancestors have been shown to affect phenotype in several organisms, including humans, mice, and the fruit fly. Whether the ancestral dietary effect is purely environmental or if there is a genetic interaction with the environment passed down for multiple generations, has not been determined previously. Here we used the fruit fly, Drosophila melanogaster, to investigate the genetic, sex-specific, and environmental effects of a high fat diet for three generations’ on pupal body weights across ten genotypes. We also tested for genotype-specific transgenerational effects on metabolic pools and egg size across three genotypes. We showed that there were substantial differences in transgenerational responses to ancestral diet between genotypes and sexes through both first and second descendant generations. Additionally, there were differences in phenotypes between maternally and paternally inherited dietary effects. We also found a treated organism’s reaction to a high fat diet was not a consistent predictor of its untreated descendants’ phenotype. The implication of these results is that, given our interest in understanding and preventing metabolic diseases like obesity, we need to consider the contribution of ancestral environmental experiences. However, we need to be cautious when drawing population-level generalization from small studies because transgenerational effects are likely to exhibit substantial sex and genotype specificity.

The Cycle of Abuse: When Victims Become Offenders

Various psychological theories exist in the literature to explain the behavior of men who commit child sex offences, including the belief that child sexual abuse (CSA) is a predisposing factor for the transition from victim to offender. These theories are, however, unable to explain the fact that while most victims of CSA are female, most perpetrators of CSA are male. The sex specificity of CSA in terms of victims and offenders suggests that the experience of CSA and its psychosocial effects may be different for boys, compared to girls. We hypothesize that CSA experiences may involve risk factors that affect the development of sexually abusive behavior for boys, rather than girls. Our aim was to determine whether the literature provides evidence of a cycle of abuse from victim to offender, and, if so, to document its characteristics. We undertook a comprehensive literature review of studies on both victims and offenders, including studies which revealed the following: age of onset of CSA, duration of abuse, gender of the abuser, the relationship between victim and abuser, grooming behaviors, the types and severity of abuse, and disclosure of abuse. While we found no evidence for the existence of a cycle of abuse for female CSA victims, we discovered evidence to support the existence of a cycle of abuse for male CSA victims who had experienced particular abuse characteristics. As an original contribution to the literature, we identified four factors that may be associated with a boy’s transition from victim to offender as well as the methodological issues to be addressed in future research. Based on criminological theories, we argue that these four factors share a common theme, that is, that they represent experiences of power (for the abuser) and powerlessness (for the victim).

Dietary omega-6 fatty acid replacement selectively impairs cardiac functional recovery after ischemia in female (but not male) rats.

A definitive understanding of the role of dietary lipids in determining cardioprotection (or cardiodetriment) has been elusive. Randomized trial findings have been variable and sex specificity of dietary interventions has not been determined. In this investigation the sex-selective cardiac functional effects of three diets enriched by omega-3 or omega-6 polyunsaturated fatty acids (PUFA) or enriched to an equivalent extent in saturated fatty acid components were examined in rats after an 8-wk treatment period. In females the myocardial membrane omega-6:omega-3 PUFA ratio was twofold higher than males in the omega-6 diet replacement group. In diets specified to be high in omega-3 PUFA or in saturated fat, this sex difference was not apparent. Isolated cardiomyocyte and heart Langendorff perfusion experiments were performed, and molecular measures of cell viability were assessed. Under basal conditions the contractile performance of omega-6 fed female cardiomyocytes and hearts was reduced compared with males. Omega-6 fed females exhibited impaired systolic resilience after ischemic insult. This response was associated with increased postischemia necrotic cell damage evaluated by coronary lactate dehydrogenase during reperfusion in omega-6 fed females. Cardiac and myocyte functional parameters were not different between omega-3 and saturated fat dietary groups and within these groups there were no discernible sex differences. Our data provide evidence at both the cardiac and cardiomyocyte levels that dietary saturated fatty acid intake replacement with an omega-6 (but not omega-3) enriched diet has selective adverse cardiac effect in females. This finding has potential relevance in relation to women, cardiac risk, and dietary management.

Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

The prevalence of Alzheimer’s disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.

Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset.

Adolescence is a unique period of development, marked by maturation of the prefrontal cortex (PFC), a region important for executive functioning. During this time, the human PFC decreases in overall volume and thickness. Likewise in adolescent rodents, losses of neurons, dendrites, dendritic spines and neurotransmitter receptors have been documented within the medial prefrontal cortex (mPFC), sometimes with sex and layer specificity. However, changes in the number of synapses during this time have not been examined. In the present study, we stereologically quantified the number of synaptophysin-immunoreactive boutons in the male and female rat mPFC across multiple time points from the juvenile period through adulthood (postnatal days (P) 25, 35, 45, 60 and 90). In females, there was a significant decrease in synaptophysin boutons between P35 and P45, coinciding with the onset of puberty. In males, there was no significant main effect of age on synaptophysin boutons; however, in both males and females, pubertal onset was associated with significant synaptic losses. These results suggest that puberty is a critical period for synaptic pruning within the rat mPFC, potentially contributing to maturation of adolescent executive function. Synapse 70:361-368, 2016. © 2016 Wiley Periodicals, Inc.