Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in the central nervous system, promoting synaptic plasticity, neurogenesis and neuroprotection. The BDNF gene ...structure is very complex and consists of multiple 5'-non-coding exons, which give rise to differently spliced transcripts, and one coding exon at the 3'-end. These multiple transcripts, together with the complex transcriptional regulatory machinery, lead to a complex and fine regulation of BDNF expression that can be tissue and stimulus specific. BDNF effects are mainly mediated by the high-affinity, tropomyosin-related, kinase B receptor and involve the activation of several downstream cascades, including the mitogen-activated protein kinase, phospholipase C-γ and phosphoinositide-3-kinase pathways. BDNF exerts a wide range of effects on neuronal function, including the modulation of activity-dependent synaptic plasticity and neurogenesis. Importantly, alterations in BDNF expression and function are involved in different brain disorders and represent a major downstream mechanism for stress response, which has important implications in psychiatric diseases, such as major depressive disorders and schizophrenia. In the present review, we have summarized the main features of BDNF in relation to neuronal plasticity, stress response and pathological conditions, and discussed the role of BDNF as a possible target for pharmacological and non-pharmacological treatments in the context of psychiatric illnesses.
Background Prenatal exposure to infectious or inflammatory insults increases the risk of neurodevelopmental disorders. Using a well-established mouse model of prenatal viral-like immune activation, ...we examined whether this pathological association involves genome-wide DNA methylation differences at single nucleotide resolution. Methods Prenatal immune activation was induced by maternal treatment with the viral mimetic poly(I:C) in middle or late gestation. Following behavioral and cognitive characterization of the adult offspring ( N = 12 per group), unbiased capture array bisulfite sequencing was combined with subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and quantitative real-time PCR analyses to quantify DNA methylation changes and transcriptional abnormalities in the medial prefrontal cortex of immune-challenged and control offspring. GO term enrichment analysis was used to explore shared functional pathways of genes with differential DNA methylation. Results Adult offspring of immune-challenged mothers displayed hyper- and hypomethylated CpGs at numerous loci and at distinct genomic regions, including genes relevant for GABAergic differentiation and signaling (e.g., DLX1, LHX5, LHX8), Wnt signaling (WNT3, WNT8A, WNT7B), and neural development (e.g., EFNB3, MID1, NLGN1, NRX2). Altered DNA methylation was associated with transcriptional changes of the corresponding genes. The epigenetic and transcriptional effects were dependent on the offspring’s age and were markedly influenced by the precise timing of prenatal immune activation. Conclusions Prenatal viral-like immune activation is capable of inducing stable DNA methylation changes in the medial prefrontal cortex. These long-term epigenetic modifications are a plausible mechanism underlying the disruption of prefrontal gene transcription and behavioral functions in subjects with prenatal infectious histories.
Serotonin (5-HT) and brain-derived neurotrophin factor (BDNF) are known to modulate behavioral responses to stress and to mediate the therapeutic efficacy of antidepressant agents through ...neuroplastic and epigenetic mechanisms. While the two systems interact at several levels, this scenario is complicated by a number of variants including brain region specificity, 5-HT receptor selectivity and timing. Based on recent insights obtained using 5-HT transporter (5-HTT) knockout rats we here set-out and discuss the crucial role of neurodevelopmental mechanisms and the contribution of transcription factors and epigenetic modifications to this interaction and its variants. 5-HTT knockout in rats, as well as the low activity short allelic variant of the serotonin transporter human polymorphism, consistently show reduced BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex. This starts during the second postnatal week, is preceded by DNA hypermethylation during the first postnatal week, and it is developmentally paralleled by reduced expression of key transcription factors. The reduced BDNF levels, in turn, affect 5-HT1A receptor-mediated intracellular signaling and thereby the serotonergic phenotype of the neurons. We propose that such a negative spiral of modifications may affect brain development and reduce its resiliency to environmental challenges during critical time windows, which may lead to phenotypic alterations that persist for the entire life. The characterization of 5-HT-BDNF interactions will eventually increase the understanding of mental illness etiology and, possibly, lead to the identification of novel molecular targets for drug development.
Abstract Aging is a physiological process characterized by a significant reduction of neuronal plasticity that might contribute to the functional defects observed in old subjects. Even if the ...neurobiological mechanisms that contribute to such impairment remain largely unknown, a role for neurotrophic molecules, such as the neurotrophin brain-derived neurotrophic factor (BDNF), has been postulated. On this basis, the purpose of this study was to provide a detailed investigation of the BDNF system, at transcriptional and translational levels, in the ventral and dorsal hippocampus and in the prefrontal cortex of middle-aged and old rats, compared with in adult animals. The expression of major players in BDNF regulation and response, including the transcription factors, calcium-responsive transcription factor, cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB), and neuronal Per Arnt Sim (PAS) domain protein 4, and the high-affinity receptor tropomyosin receptor kinase B (TrkB), was also analyzed. Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription, impaired protein synthesis and processing, and decreased activation of the TrkB receptors. These modifications might contribute to the cognitive deficits associated with aging and suggest that pharmacological strategies aimed at restoring reduced neurotrophism might be useful to counteract age-related cognitive decline.
Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative ...impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.
Neuronal dysfunctions in the cortical GABAergic system have been widely documented in neuropsychiatric disorders with prenatal infectious etiologies, including schizophrenia. At least some of these ...abnormalities may stem from transcriptional impairments in the GABAergic transcriptome. However, the extent to which prenatal exposure to immune challenge can induce long-term alterations in GABAergic gene transcription remains largely elusive. Here, we use an established mouse model of prenatal immune activation induced by maternal gestational administration of the viral mimetic poly(I:C) (= polyriboinosinic-polyribocytidilic acid) to demonstrate that prenatal immune activation causes maturation-dependent alterations in prefrontal GABAergic gene expression. The spectrum of abnormalities included altered mRNA expression levels of enzymes regulating γ-aminobutyric acid (GABA) biosynthesis (glutamic acid decarboxylase 65-kDa GAD65 and GAD67), vesicular GABA transporter (VGAT), alpha-subunits of the GABA(A) receptor (α2, α3, α4, and α5), and the chloride transporters sodium-potassium-chloride cotransporter 1 and potassium-chloride cotransporter 2. Additional western blot analyses confirmed the deficits in prefrontal GAD65/GAD67 and VGAT expression at the protein level. Intriguingly, the prefrontal GABAergic transcriptome was found to be more strongly affected in adult compared with peripubertal offspring born to immune-challenged mothers, and these age-dependent changes in GABAergic gene expression were paralleled by an adult onset of working memory deficiency. Collectively, our data emphasize a critical impact of prenatal immune-related insults on long-term GABAergic changes relevant to neuropsychiatric disorders with prenatal infectious etiologies, especially for those with delayed onset in early adulthood.
Exposure to adversities during early life stages (early life adversities - ELA), ranging from pregnancy to adolescence, represents a major risk factor for the vulnerability to mental disorders. ...Hence, it is important to understand the molecular and functional underpinning of such relationship, in order to develop strategies aimed at reducing the psychopathologic burden associated with ELA, which may eventually lead to a significant improvement in clinical practice. In this review, we will initially recapitulate clinical and preclinical evidence supporting the link between ELA and psychopathology and we will primarily discuss the main biological mechanisms that have been described as potential mediators of the effects of ELA on the psychopathologic risk, including the role for genetic factors as well as sex differences. The knowledge emerging from these studies may be instrumental for the development of novel therapeutic strategies aimed not only at correcting the deficits that emerge from ELA exposure, but also in preventing the manifestation of a full-blown psychopathologic condition. With this respect, we will specifically focus on adolescence as a key time frame for disease onset as well as for early therapeutic intervention. We believe that incorporating clinical and preclinical research data in the context of early life adversities can be instrumental to elucidate the mechanisms contributing to the risk for psychopathology or that may promote resilience. This will ultimately allow the identification of ‘at risk’ individuals who may benefit from specific forms of interventions that, by interfering with disease trajectories, could result in more benign clinical outcomes.
Cytokines are key regulatory mediators involved in the host response to immunological challenges, but also play a critical role in the communication between the immune and the central nervous system. ...For this, their expression in both systems is under a tight regulatory control. However, pathological conditions may lead to an overproduction of pro-inflammatory cytokines that may have a detrimental impact on central nervous system. In particular, they may damage neuronal structure and function leading to deficits of neuroplasticity, the ability of nervous system to perceive, respond and adapt to external or internal stimuli. In search of the mechanisms by which pro-inflammatory cytokines may affect this crucial brain capability, we will discuss one of the most interesting hypotheses: the involvement of the neurotrophin brain-derived neurotrophic factor (BDNF), which represents one of the major mediators of neuroplasticity.
Summary Although stress represents the major environmental element of susceptibility for mood disorders, the relationship between stress and disease remains to be fully established. In the present ...article we review the evidence in support for a role of neuronal plasticity, and in particular of neurotrophic factors. Even though decreased levels of norepinephrine and serotonin may underlie depressive symptoms, compelling evidence now suggests that mood disorders are characterized by reduced neuronal plasticity, which can be brought about by exposure to stress at different stages of life. Indeed the expression of neurotrophic molecules, such as the neurotrophin BDNF, is reduced in depressed subjects as well as in experimental animals exposed to adverse experience at early stages of life or at adulthood. These changes show an anatomical specificity and might be sustained by epigenetic mechanisms. Pharmacological intervention may normalize such defects and improve neuronal function through the modulation of the same factors that are defective in depression. Several studies have demonstrated that chronic, but not acute, antidepressant treatment increases the expression of BDNF and may enhance its localization at synaptic level. Antidepressant treatment can normalize deficits in neurotrophin expression produced by chronic stress paradigms, but may also alter the modulation of BDNF under acute stressful conditions. In summary, there is good agreement in considering neuronal plasticity, and the expression of key proteins such as the neurotrophin BDNF, as a central player for the effects of stress on brain function and its implication for psychopathology. Accordingly, effective treatments should not limit their effects to the control of neurotransmitter and hormonal dysfunctions, but should be able to normalize defective mechanisms that sustain the impairment of neuronal plasticity.
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