Brain-derived Neurotrophic Factor Deficits Research Articles

Expression of activity-regulated transcripts in pyramidal neurons across the cortical visuospatial working memory network in unaffected comparison individuals and individuals with schizophrenia

Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by multiple cortical regions including the primary (V1) and association (V2) visual, posterior parietal (PPC) and dorsolateral prefrontal (DLPFC) cortices. In these regions, parvalbumin (PV) or somatostatin (SST) GABA neurons are altered in SZ as reflected in lower levels of activity-regulated transcripts. As PV and SST neurons receive excitatory inputs from neighboring pyramidal neurons, we hypothesized that levels of activity-regulated transcripts are also lower in pyramidal neurons in these regions. Thus, we quantified levels of four activity-regulated, pyramidal neuron-selective transcripts, namely adenylate cyclase-activating polypeptide-1 (ADCYAP1), brain-derived neurotrophic factor (BDNF), neuronal pentraxin-2 (NPTX2) and neuritin-1 (NRN1) mRNAs, in V1, V2, PPC and DLPFC from unaffected comparison and SZ individuals. In SZ, BDNF and NPTX2 mRNA levels were lower across all four regions, whereas ADCYAP1 and NRN1 mRNA levels were lower in V1 and V2. The regional pattern of deficits in BDNF and NPTX2 mRNAs was similar to that in transcripts in PV and SST neurons in SZ. These findings suggest that lower activity of pyramidal neurons expressing BDNF and/or NPTX2 mRNAs might contribute to alterations in PV and SST neurons across the vsWM network in SZ.

Astrocytes and brain-derived neurotrophic factor (BDNF)

Astrocytes are emerging in the neuroscience field as crucial modulators of brain functions, from the molecular control of synaptic plasticity to orchestrating brain-wide circuit activity for cognitive processes. The cellular pathways through which astrocytes modulate neuronal activity and plasticity are quite diverse. In this review, we focus on neurotrophic pathways, mostly those mediated by brain-derived neurotrophic factor (BDNF). Neurotrophins are a well-known family of trophic factors with pleiotropic functions in neuronal survival, maturation and activity. Within the brain, BDNF is the most abundantly expressed and most studied of all neurotrophins. While we have detailed knowledge of the effect of BDNF on neurons, much less is known about its physiology on astroglia. However, over the last years new findings emerged demonstrating that astrocytes take an active part into BDNF physiology. In this work, we discuss the state-of-the-art knowledge about astrocytes and BDNF. Indeed, astrocytes sense extracellular BDNF through its specific TrkB receptors and activate intracellular responses that greatly vary depending on the brain area, stage of development and receptors expressed. Astrocytes also uptake and recycle BDNF / proBDNF at synapses contributing to synaptic plasticity. Finally, experimental evidence is now available describing deficits in astrocytic BDNF in several neuropathologies, suggesting that astrocytic BDNF may represent a promising target for clinical translation.

Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism.

Environmental factors, such as medication during pregnancy, are one of the major causes of autism spectrum disorder (ASD). Valproic acid (VPA) intake during pregnancy has been reported to dramatically elevate autism risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains to be determined whether and how alterations in the excitatory/inhibitory (E/I) balance contribute to VPA-induced ASD in a mouse model. In the present study, we explored changes in the E/I balance during different developmental periods in a VPA mouse model. We found that typical markers of pre- and postsynaptic excitatory and inhibitory function involved in E/I balance markedly decreased during development, reflecting difficulties in the development of synaptic plasticity in VPA-exposed mice. The expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the formation and maturation of glutamatergic and GABAergic synapses during postnatal development, was severely reduced in the VPA-exposed group. Treatment with exogenous BDNF during the critical E/I imbalance period rescued synaptic functions and autism-like behaviors, such as social defects. With these results, we experimentally showed that social dysfunction in the VPA mouse model of autism might be caused by E/I imbalance stemming from BDNF deficits during the developmental stage.

Human \u03b1-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy

Anxiety and depression affect 35–50% of patients with Parkinson’s disease (PD), often precede the onset of motor symptoms, and have a negative impact on their quality of life. Dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD and contributes to a variety of non-motor symptoms. Furthermore, α-synuclein (α-Syn) aggregates were identified in raphe nuclei in the early stages of the disease. However, there are very few animal models of PD-related neuropsychiatric disorders. Here, we develop a new mouse model of α-synucleinopathy in the 5-HT system that mimics prominent histopathological and neuropsychiatric features of human PD. We showed that adeno-associated virus (AAV5)-induced overexpression of wild-type human α-Syn (h-α-Syn) in raphe 5-HT neurons triggers progressive accumulation, phosphorylation, and aggregation of h-α-Syn protein in the 5-HT system. Specifically, AAV5-injected mice displayed axonal impairment in the output brain regions of raphe neurons, and deficits in brain-derived neurotrophic factor (BDNF) expression and 5-HT neurotransmission, resulting in a depressive-like phenotype. Intracerebroventricular treatment with an indatraline-conjugated antisense oligonucleotide (IND-ASO) for four weeks induced an effective and safe reduction of h-α-Syn synthesis in 5-HT neurons and its accumulation in the forebrain, alleviating early deficits of 5-HT function and improving the behavioural phenotype. Altogether, our findings show that α-synucleinopathy in 5-HT neurons negatively affects brain circuits that control mood and emotions, resembling the expression of neuropsychiatric symptoms occurring at the onset of PD. Early preservation of 5-HT function by reducing α-Syn synthesis/accumulation may alleviate PD-related depressive symptoms.

Deep brain stimulation improved depressive-like behaviors and hippocampal synapse deficits by activating the BDNF/mTOR signaling pathway

Our previous study demonstrated that acute deep brain stimulation (DBS) in the ventromedial prefrontal cortex (vmPFC) remarkably improved the depressive-like behaviors in a rat model of chronic unpredictable mild stress (CUS rats). However, the mechanisms by which chronic DBS altered depressive-like behaviors and reversed cognitive impairment have not been clarified. Recent work has shown that deficits in brain-derived neurotrophic factor (BDNF) and its downstream proteins, including mammalian target of rapamycin (mTOR), might be involved in the pathogenesis of depression. Therefore, we hypothesized that the antidepressant-like and cognitive improvement effects of DBS were achieved by activating the BDNF/mTOR pathway. CUS rats received vmPFC DBS at 20 Hz for 1 h once a day for 28 days. After four weeks of stimulation, the rats were assessed for the presence of depressive-like behaviors and euthanized to detect BDNF/mTOR signaling using immunoblots. DBS at the vmPFC significantly ameliorated depressive-like behaviors and spatial learning and memory deficits in the CUS rats. Furthermore, DBS restored the reduced synaptic density in the hippocampus induced by CUS and increased the expression or activity of BDNF, Akt, and mTOR in the hippocampus. Thus, the antidepressant-like effects and cognitive improvement produced by vmPFC DBS might be mediated through increased activity of the BDNF/mTOR signaling pathway.

Targeting Brain-Derived Neurotrophic Factor (BDNF) - An Important Strategy to Alzheimer's Disease

Many theories have been proposed to explain why candidate disease-modifying drugs (DMTs) for Alzheimer's disease (AD) failed. Late initiation of treatments during AD development, inappropriate drug dosages, incorrect selection of main therapeutic targets, and primarily inadequate understanding of the complex pathophysiology of AD are the most prominent ones. Reduced expression of Brain Derived Neurotrophic Factor (BDNF) is essential in the pathogenesis of Alzheimer's disease. BDNF plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. It can be a novel target for the treatment of the disease. In Alzheimer's disease, the hippocampus, parietal, entorhinal, and frontal cortex all have the most extreme BDNF deficits. Lower levels of BDNF can be linked to neuronal death, masking any gene-related effects. High BDNF levels have been attributed to a lower risk of dementia and Alzheimer's. Improvements in BDNF levels imparted by exercise, plant based drugs, trkB receptor agonist and BDNF enhancer drug have been proved to enhance cognitive performance. Plant-based products and nutraceuticals can boost BDNF levels. Polyphenols are essential plant compounds with a wide range of therapeutic potentials. Flavonoids like calycosin, genistein, isorhamnetin, and luteolin have been shown to affect the level of BDNF. Curcumin, a compound derived from spice turmeric (curcuma longa), has a variety of biological functions in the brain, including antidepressant properties which also increase BDNF level in the hippocampus. Riluzole is used to treat amyotrophic lateral sclerosis (ALS). In a depression model with chronic corticosteroid intake, riluzole also restores hippocampal BDNF levels. Evidence indicates that BDNF deficiency plays a role in the pathogenesis of Alzheimer's disease. Drugs used to treat Alzheimer's disease have the unintended property of modulating BDNF levels in brain regions specifically involved in the disease's pathophysiology. The discovery of molecules that precisely control BDNF in particular cellular phenotypes could increase the effectiveness of therapy against AD.

Low BDNF levels in serum are associated with cognitive impairments in medication-naïve patients with current depressive episode in BD II and MDD

ObjectiveThis study aimed to investigate the role of Brain-derived neurotrophic factor (BDNF) in clinical and cognitive outcomes in medication-naïve patients with Bipolar type II disorder (BD II) and Major depressive disorder (MDD). Methods45 outpatients with BD II, 40 outpatients with MDD and 40 healthy controls (HCs) were recruited, and sociodemographic and clinical data were collected. Their BDNF serum levels were measured and analyzed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). ResultsBDNF levels were significantly lower in BD II patients than in MDD patients and HCs (p = 0.001). BD II and MDD patients had similar cognitive performance deficits shown on Attention (p = 0.001), Delayed memory (p = 0.001), and RBANS total score (p = 0.001). BDNF levels were positively associated with Visuospatial / constructional and Stroop color-word in BD II group, and with language in MDD group. The area under the curve (AUC) of the ROC analysis in BD II vs. MDD was 0.664, therefore, BDNF levels could not distinguish BD II from MDD. ConclusionOur study showed the decreased serum BDNF in MDD and BD II patients, suggesting BDNF may be involved in the pathophysiology of MDD and BD II. BDNF and cognitive deficits are both of low efficiency in distinguishing BD II from MDD. Decrease of BDNF may potentially indicate cognitive dysfunction in BD II and MDD patients with a current depressive episode.

BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment

Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF’s role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/−) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/− mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/− mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/− mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

Voluntary exercise and estradiol reverse ovariectomy-induced spatial learning and memory deficits and reduction in hippocampal brain-derived neurotrophic factor in rats

Ample evidences have demonstrated the beneficial effects of physical exercise on cognitive functions such as learning and memory. It is well established that female sex hormones have an important role in regulating learning and memory. This study was designed to investigate the effects of voluntary exercise and estrogen replacement on learning and memory deficits and reduction in hippocampal brain derived neurotrophic factor (BDNF) levels induced by ovariectomy. Ovariectomized rats were given daily vehicle or 17 β-estradiol (20 μg/kg) and allowed to freely exercise in a running wheel over the course of 2 weeks. After this period, they were trained and tested on a water-maze spatial task for 5 consecutive days, followed by a probe test one day later. At the end of the behavioral tests, all animals were decapitated and their hippocampal levels of BDNF were measured. Ovariectomy impaired spatial learning and memory and reduced hippocampal BDNF levels. Exercise significantly improved performance during both training and the retention of the water-maze task and increased hippocampal BDNF. Exercise, 17 β-estradiol and their combination recovered the impairing effects of ovariectomy on learning and memory performance. The combined treatment did not produce stronger effect than either exercise or 17 β-estradiol alone. Our findings provide an important evidence about positive influences of regular exercise and estrogen treatment against cognitive and BDNF deficits induced in ovariectomized rats, an experimental model of menopause.

Impact of Chronic BDNF Depletion on GABAergic Synaptic Transmission in the Lateral Amygdala.

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABAA-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF+/−). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF+/− mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF+/− mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF+/− mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.

Improvement of BDNF signalling by P42 peptide in Huntington's disease.

Huntington's disease (HD) is caused by a mutation in the Huntingtin (HTT) protein. We previously reported that the 23aa peptide of HTT protein, P42, is preventing HD pathological phenotypes, such as aggregation, reduction of motor performances and neurodegeneration. A systemic treatment with P42 during the pre-symptomatic phase of the disease showed therapeutic potential in R6/2 mice. We here tested P42 effects when administered during the post-symptomatic phase. The P42 treatment alleviated deficits in motor performances, even when symptoms have already started. Because changes in the level and activity of brain-derived neurotrophic factor (BDNF) have been shown to play a central role in HD, we analysed the influence of P42 on BDNF deficit and associated phenotypes. Our data suggest that P42 is involved in the spatio-temporal control of bdnf and trkB mRNA and their protein levels. Related to this enhancement of BDNF-TrkB signalling, R6/2 mice treated with P42, exhibit reduced anxiety, better learning and memory performances, and better long-term potentiation (LTP) response. Finally we identified a direct influence of P42 peptide on neuronal plasticity and activity. These results suggest that P42 offers an efficient therapeutic potential not only by preventing aggregation of mutant HTT at early stages of the disease, but also by favouring some physiological functions of normal HTT, as P42 is naturally part of it, at the different stages of the disease. This makes P42 peptide potentially suitable not only to prevent, but also to treat HD.

P.1.010 - Brain-derived neurotrophic factor enhances glutamic acid decarboxylase and perineuronal net maturation in mouse primary cortical cultures

Schizophrenia is a debilitating mental illness which affects approximately 1% of the global population, and is characterised by positive (e.g. hallucinations) and negative (e.g. anhedonia) symptoms, combined with cognitive deficits. Evidence suggests diminished cortical inhibitory drive as a major contributing factor in schizophrenia pathophysiology. Reductions in glutamic acid decarboxylase (GAD65/67) and deficits in the extracellular matrix structures, perineuronal nets (PNNs), which enwrap parvalbumin-containing interneurons have been observed in patients [1,2]. Members of the c-Jun N-Terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) and their upstream kinase MKK7 have been implicated in neocortical development. Interestingly, MAP2K7 (encoding MKK7) has been implicated as a candidate risk gene for schizophrenia [3]. However, the impact of disrupted MAP2K7-JNK signalling on GABAergic interneuron development remains elusive. Reduced levels of brain-derived neurotrophic factor (BDNF) have also been found in patients [4]. Previous research highlights BDNF as a promoter of GABAergic maturation in hippocampal neurons [5]. Consequently, altered BDNF activity could result in abnormal cortical circuitry development and contribute to the cortical neuronal dysfunction underlying schizophrenia. Here we study the effects of BDNF on the development of primary cortical GABAergic interneurons and surrounding PNNs along with the possible involvement of JNK signalling. Mouse primary cortical neuronal cultures were treated at 7 days in vitro with either vehicle, BDNF (50 ng/ml), JNK inhibitor (SP600125, 5 μM) or BDNF+JNK inhibitor. Subsequently, immunofluorescent-cytochemistry (ICC) was performed. PNN development was assessed using Wisteria floribunda agglutinin (WFA) lectin which labels interneuron PNNs. Cultures were double-labelled with GAD65/67. Normalised intensity data (in relative optical density) were expressed as a percentage of vehicle and analysed via three-way ANOVA with Tukey post-hoc multiple comparisons with results considered significant if p Analysis of WFA staining intensity revealed significant main effects of BDNF (F1, 982 = 45.46, p Our data demonstrate that BDNF increased GAD65/67 levels and PNN density in developing cortical interneurons. Our data suggest this enhancing effect of BDNF on GAD65/67 and PNN maturation is dependent on JNK signalling. Given evidence of reduced BDNF levels in schizophrenia patients, we speculate that impairments in MAP2K7-JNK signalling may be linked with functional BDNF deficits in schizophrenia and that BDNF disruption could be involved in disorder aetiology and pathophysiology.

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats.

Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer's disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear. The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. Rats were exposed randomly to chronic mild stressors for 7weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50mg/kg) was administered daily during the last 2weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus. We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine. Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits.

Integrin-linked Kinase is Essential for Environmental Enrichment Enhanced Hippocampal Neurogenesis and Memory.

Environment enrichment (EE) has a variety of effects on brain structure and function. Brain-derived neurotrophic factor (BDNF) is essential for EE-induced hippocampal neurogenesis and memory enhancement. However, the intracellular pathway downstream of BDNF to modulate EE effects is poorly understood. Here we show that integrin-linked kinase (ILK) levels are elevated upon EE stimuli in a BDNF-dependent manner. Using ILK-shRNA (siILK) lentivirus, we demonstrate that knockdown of ILK impairs EE-promoted hippocampal neurogenesis and memory by increasing glycogen synthase kinase-3β (GSK3β) activity. Finally, overexpressing ILK in the hippocampus could rescue the neurogenesis and memory deficits in BDNF+/− mice. These results indicate that ILK is indispensable for BDNF-mediated hippocampal neurogenesis and memory enhancement upon EE stimuli via regulating GSK3β activity. This is a new insight of the precise mechanism in EE-enhanced memory processes and ILK is a potentially important therapeutic target that merits further study.

The effects of lobeline on depression-like behavior and hippocampal cell proliferation following chronic stress in mice

We have reported that brain nicotinic acetylcholine receptor (nAChR) ligand lobeline has antidepressant-like effects in mice. The present study examined the effects of lobeline on chronic unpredictable stress (CUS)-induced depression-like behavior, deficits in brain-derived neurotrophic factor (BDNF) expression and cell proliferation in the hippocampus. Adult C57BL/6J mice were exposed to CUS for 6 weeks. Lobeline (1 or 4mg/kg, s.c.) or saline was administered once daily during the last 14 days of CUS. CUS-exposed mice showed increased immobility time in the FST compared to control. Pretreatment with lobeline (1mg/kg) significantly reduced immobility time in the CUS-exposed mice. Twenty-four hour following lobeline or saline treatment, BDNF expression or cell proliferation was measured in the hippocampus using Western blotting and bromodeoxyuridine immunohistochemistry, respectively. Lobeline (1mg/kg) treatment prevented CUS-induced reduction in BDNF expression and cell proliferation in the hippocampus. Overall, our findings suggest that antidepressant-like effects of lobeline could involve nAChR mediated signaling, BDNF expression, and/or hippocampal cell proliferation.

A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome.

Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice.

Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to critically influence brain development and functions. Dietary supplementation with n-3 PUFAs has been suggested as a non-pharmacological therapy for a number of developmental disorders, e.g., autistic spectrum disorders (ASD), but human studies so far have led to conflicting results. Furthermore, it has been hypothesized that the therapeutic impact of n-3 PUFAs on these disorders might be explained by their anti-inflammatory properties and their promoting effects on synaptic function and plasticity, but no clear evidence has been produced in this direction. We evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD. Fmr1-KO and wild-type mice were provided with a diet enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors. The brain expression of several cytokines and of brain-derived neurotrophic factor (BDNF) was concomitantly assessed as inflammatory and synaptic markers. n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory. n-3 PUFAs also rescued most of the neuroinflammatory imbalances of KOs, but had a limited impact on their BDNF deficits. These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS and potentially for ASD, suggesting a major mediating role of neuroinflammatory mechanisms.

Transcriptome profiling analysis of the mechanisms underlying the BDNF Val66Met polymorphism induced dysfunctions of the central nervous system

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism affects postnatal behaviors and is associated with a variety of neuropsychiatric disorders. However, the mechanisms underlying the BDNF(Met) variant induced dysfunctions of the central nervous system remain obscure. In order to identify the candidate genes and pathways responsible for the dysfunctions associated with this BDNF variation, we analyzed the expression of genes in the hippocampus, prefrontal cortex, and amygdala of the BDNF(Met) variant mice in comparison with the wild-type mice using Illumina bead microarray. Transcriptome profiling analysis revealed region-distinctive and gene-dose dependent changes of gene expression associated with the BDNF(Met) variant. BDNF(Met) variant mice exhibited altered expression of genes associated with translational machinery, neuronal plasticity and mitochondrial function based on the gene ontology (GO) annotation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the chemokine, cell adhesion, ubiquitin-proteosome and wnt signaling pathways were altered in the BDNF(Met) variant mice brain. Finally, the CX3CL1/CX3CR1 signaling was identified to be impaired in the hippocampus and microinjection of CX3CL1 into the hippocampus could rescue the hippocampal dependent memory deficits in BDNF(Met/Met) mice, indicating that CX3CL1 may be an effective treatment option for memory disorders in humans with this genetic BDNF variation. These findings will help us further understanding the molecular mechanisms involved in the BDNF(Met) associated behavior and neuroanatomy alternations.

Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment

Development of anxiety-like behaviours during ethanol withdrawal has been correlated with increased histone deacetylase (HDAC) activity and decreased brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc) gene expression in the amygdala. Furthermore, HDAC-mediated histone modifications play a role in synaptic plasticity. In this study we used the HDAC inhibitor trichostatin A (TSA) to determine whether HDAC inhibition could prevent ethanol withdrawal-induced deficits in dendritic spine density (DSD), BDNF or Arc expression in the amygdala of rats. It was found that decreased BDNF and Arc expression in the central (CeA) and medial nucleus of amygdala (MeA), observed during withdrawal after chronic ethanol exposure, were normalized following acute TSA treatment. TSA treatment was also able to attenuate anxiety-like behaviours during ethanol withdrawal and correct the observed decrease in DSD in the CeA and MeA of ethanol-withdrawn rats. Taken together, these findings demonstrate that correcting the deficits in histone acetylation through TSA treatment also amends downstream synaptic plasticity-related deficits such as BDNF and Arc expression, and DSD in the CeA and MeA as well as attenuates anxiety-like behaviours in rats during withdrawal after chronic ethanol exposure.

Abnormal Expression of Cerebrospinal Fluid Cation Chloride Cotransporters in Patients with Rett Syndrome

ObjectiveRett Syndrome is a progressive neurodevelopmental disorder caused mainly by mutations in the gene encoding methyl-CpG-binding protein 2. The relevance of MeCP2 for GABAergic function was previously documented in animal models. In these models, animals show deficits in brain-derived neurotrophic factor, which is thought to contribute to the pathogenesis of this disease. Neuronal Cation Chloride Cotransporters (CCCs) play a key role in GABAergic neuronal maturation, and brain-derived neurotrophic factor is implicated in the regulation of CCCs expression during development. Our aim was to analyse the expression of two relevant CCCs, NKCC1 and KCC2, in the cerebrospinal fluid of Rett syndrome patients and compare it with a normal control group.MethodsThe presence of bumetanide sensitive NKCC1 and KCC2 was analysed in cerebrospinal fluid samples from a control pediatric population (1 day to 14 years of life) and from Rett syndrome patients (2 to 19 years of life), by immunoblot analysis.ResultsBoth proteins were detected in the cerebrospinal fluid and their levels are higher in the early postnatal period. However, Rett syndrome patients showed significantly reduced levels of KCC2 and KCC2/NKCC1 ratio when compared to the control group.ConclusionsReduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective.