Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway

Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats

Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events

Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood

Plasma amino acids and neopterin in healthy persons with Down’s syndrome

In persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism

Sex Differences in the Enduring Effects of Social Deprivation during Adolescence in Rats : Implications for Psychiatric Disorders

The exposure to adverse environmental situations during sensitive periods of development may induce re-organizational effects on different systems and increase the vulnerability to develop psychiatric disorders later in life. The adolescent period has been demonstrated extremely susceptible to stressful events. However, most of the studies focused on the immediate effects of stress exposure and few of them investigated sex differences. This raised the question if these modulations might also be long-lasting and how the differential maturational events taking place during adolescence between males and females might have a role in the detrimental effects of stress. Given the importance of social play for the right maturation of behavior during adolescence, we used the preclinical model of social deprivation, based on the lack of all social contacts, for four weeks after weaning, followed by re-socialization until adulthood. We found that both male and female animals reared in isolation during adolescence developed an anhedonic phenotype at adulthood, without any impairments in the cognitive domain. At molecular level, these functional changes were associated with sex-specific impairments in the expression of neuroplastic markers as well as of hypothalamic\u2013pituitary\u2013adrenal axis-related genes. Lastly, we also reported anatomically-selective changes associated with the enduring effects of social isolation

Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia

Background: The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study. Methods: The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease. Results: We found that the C allele may alter a consensus sequence for the transcription factor NF-\u3baB and that its frequency was higher in patients than in control subjects (p = .0085). The genotype distribution also was different, with p = .034 (if C allele dominant, p = .0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076). Conclusions: The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia

BDNF transcripts modulation in the blood of subjects exposed to childhood trauma history

Adverse influences, particularly early in development, can result in permanent changes in physiology and metabolism, which result in increased disease risk in adulthood. Childhood trauma experiences have been indeed found able to modulate brain structure and functions through alterations in neuroplasticity [1]. Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin that plays a crucial role in neuronal development and plasticity\u37e it is involved in the effects of stress and also in the pathogenesis of several mental disorders. The human BDNF gene is very complex and it consists of several transcripts that are all characterized by the presence of the common coding exon at the 3\u2019end [2,3]. To date no information regarding the expression of BDNF transcripts in the blood and of their possible modulation by stressful experiences is available. The aim of this study was to characterize the expression of BDNF transcripts in the blood of human subjects and investigate their modulation in association to exposure to stressful life experiences. We have measured total BDNF mRNA levels through Real Time PCR in peripheral blood of adult subjects (n=40) clinically assessed for exposure during childhood to sexual, emotional and/or physical trauma by childhood trauma questionnaire. We found a significant reduction in the mRNA levels of total BDNF in the blood of subjects exposed to childhood trauma versus not exposed subjects (p<0.05, 1232%). Then, to identify the BDNF transcript able to contribute to this BDNF modulation, we assessed the expression levels of the different BDNF transcript in the blood and we found that only transcripts IV and IX were well expressed. Thus, we focused our subsequent analyses on these transcripts and we evaluated by Real Time PCR their modulation in association with childhood trauma events. We found a significant modulation of both the transcripts, although a more pronounced effect was observed for transcript IV ( 1271%, p<0.05 for transcript IV\u37e 1235%, p<0.05 for transcript IX). Share Like 0 Tweet. In order to better characterize BDNF variants modulation we measured the levels of total BDNF and of the transcript IV and IX in an in vitro model represented by human hippocampal progenitors stem cells (HPSc) that we treated for three days during proliferation phase. Gene expression analyses were performed after 10 days of differentiation. We found that BDNF total levels and transcript IV and IX were downregulated also in HPC treated with cortisol (total BDNF 1225%, p<0.05\u37e transcript IV 1219%, p<0.05\u37e transcript IX 1227%, p<0.05). In order to investigate the molecular mechanisms underlying these long lasting changes in BDNF we are evaluating the role of DNA methylation and miRNAs as possible epigenetic mechanisms. These data indicate that BDNF levels are reduced in the peripheral blood of subjects exposed to childhood trauma and that similar modulation occurs in neurons. BDNF variants IV and IX are the transcripts that contribute to BDNF modulation and a better characterization of their modulation may identify novel target for preventative therapies in subjects exposed to trauma and thus at higher risk to develop psychiatric illnesses in adulthood

Lymphomonocyte alpha-synuclein levels in aging and in Parkinson disease

In this study we employed an ELISA assay to measure alpha-synuclein protein in lymphomonocytes from 78 PD patients and 78 controls. We correlated protein levels with demographic and clinical characteristics and with the chymotryptic and tryptic activities of the 20S proteasome. Alpha-synuclein levels were not significantly different between patients and controls. In control subjects, alpha-synuclein protein levels increased significantly with age and were significantly higher in men compared to women. Proteasome activity was not significantly different between cases and controls. In control group, the 20S chymotryptic activity tended to decrease significantly with increasing age, though it was not correlated to alpha-synuclein levels. The 20S tryptic activity was not significantly correlated to age, but was inversely correlated to alpha-synuclein levels. Our findings suggest that alpha-synuclein levels in lymphomonocytes are affected by age, gender, and by the 20S proteasome activity in control subjects, but they are not useful as a diagnostic biomarker for PD