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Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients

Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients Dear Editors, Brain-derived neurotrophic factor (BDNF), the most abundant neurotrophin in the brain, promotes the growth and maintenance of intercellular connections, serves as a neurotransmitter modulator, and participates in plasticity mechanisms, such as long-term potentiation and learning (Shoval and Weizman, 2005). Consequently, abnormal BDNF signaling can influence neuronal differentiation and synaptic function leading to altered brain development and functioning. The ability of BDNF to cross the blood–brain barrier (Pan et al., 1998) suggests that blood serum BDNF levels may reflect BDNF levels in the brain. However, reports about BDNF levels in the serum of schizophrenic patients have been somewhat inconsistent. Thus, an increase, no change, or a reduction in the concentration of BDNF in the blood of schizophrenics has been reported (Jockers-Scherübl et al., 2004; Pirildar et al., 2004; Toyooka et al., 2002). Post-treatment serum BDNF levels were not significantly different when compared with the baseline levels in schizophrenia patients (Pirildar et al., 2004). In turn, BDNF plasma levels in first-episode bipolar disorder patients have not yet been characterized. Here, we have analyzed the plasma level of BDNF in both first-episode schizophrenia and bipolar disorder patients upon admission to hospital and at various stages during a 1-year follow-up. This study consisted of 48 patients (mean age ± S.E. M., 23.7 ± 1 years) from the health catchment area of Vitoria (Alava, Spain), who experienced a first psychotic episode during the period 2002–2004. This sample of patients represents all first-episode patients that needed hospitalization and gave informed consent (75% of total) to participate in the study. There were no differences in age, gender, or clinical symptoms between patients included and excluded. Diagnoses were made at 12 months using the Structured Clinical Interview for DSM IV, SCID-I. 21 patients were diagnosed with schizophrenia, 14 with bipolar disorder, and the remaining 13 with non-specified psychotic disorders. Patients were treated after the first episode with atypical antipsychotics (62–68%), with lithium or other mood stabilizers together with atypical antipsy-chotics (23–26%), with typical antipsychotics (7–11%), or received no treatment (2–4%). Ranges in each treatment group indicate changes in the drugs administered initially at the onset of symptoms and during the first year of illness. Blood samples were collected upon arrival at the hospital emergency room and at 1, 6, and 12 months later, using glass whole-blood tubes containing K3-EDTA. Plasma was isolated by centrifugation …

Serum IgG Antibodies Against the NR1 Subunit of the NMDA Receptor Not Detected in Schizophrenia

To the Editor: A consensus exists that schizophrenia is not a single disease, but the final pathway of a variety of still unknown neurobiological derangements. Recently, several treatable autoimmune brain disorders have been identified presenting with psychotic symptoms that, in some cases, resemble those found in schizophrenia (1). Antibodies target synaptic proteins, interrupting synaptic transmission in brain networks supporting cognition and emotion. Particularly relevant are auto-antibodies against the NR1 subunit of the N-acetyl methyl D-aspartate receptor (NMDAR), which result in diminished NMDAR activity, now considered a hallmark of schizophrenia (2). In patients harboring these antibodies, initial psychiatric symptoms are usually followed by dyskinetic movements or seizures and decreased respiratory drive, with a reduced level of consciousness, often requiring intensive care (1). However, it could be postulated that a limited form of the disease may result in a milder syndrome, akin to schizophrenia. We tested this hypothesis using sera from patients with their first psychotic episode referred to the regional psychiatric center of the province of Alava, Spain, and from healthy controls. All were enrolled after written informed consent according to protocols approved by the local IRB. Blood was drawn and sera were frozen for subsequent study, blinded to patient-control status. After a one-year follow up, sera of patients who then met DSM-IV-TR criteria for schizophrenia-spectrum disorders were tested for antibodies to NR1 and other cell surface antigens using three criteria (immunohistochemistry on rat brain slices and dissociated rodent hippocampal neurons, and a cell-based assay in which HEK cells recombinantly express NMDAR), as previously reported (1). Patients (n=80) and healthy controls (n=40) did not differ statistically in age (29.4±9.9 and 30.7±9.4 years), or sex (28 and 38 percent women). Anti-NR1 IgG antibodies were not detected in either group. Both had four cases with sera reactive to other, still unidentified, neuronal surface antigens. Our findings and a study of seven patients with schizophrenia (3) fail to support the hypothesis that NMDAR IgG antibodies are present in the sera of patients with schizophrenia. Although another study (4) did report NMDAR antibodies in the sera of some schizophrenia patients, it was performed without a control group and test specificity was lower (only one of the above criteria was applied); differences in the clinical diagnosis could also explain the discrepant findings. It should be noted, however, that our study does not rule out that some patients could have antibodies only in cerebrospinal fluid, but not in serum (1). Additionally, antibodies could be present in patients with acute psychosis not meeting DSM-IV diagnostic criteria at one-year.

Decreased levels of plasma glutamate in patients with first-episode schizophrenia and bipolar disorder

A variety of studies have suggested that glutamatergic neurotransmission is altered in schizophrenia and bipolar disorder. Here, we tested if plasma glutamate levels are altered in 56 patients diagnosed with schizophrenia, bipolar disorder or non-specified psychosis at the first psychotic episode and at various stages during one-year follow-up. A decrease in the levels of plasma glutamate was observed in all groups of patients at the first psychotic episode. Furthermore, plasma glutamate levels were restored after treatment in all instances. Decreased plasma glutamate levels at first psychotic episodes may reflect impaired glutamate signaling during the initial stages of schizophrenia and bipolar disorder.

Relationship between negative symptoms and plasma levels of insulin-like growth factor 1 in first-episode schizophrenia and bipolar disorder patients.

Previous studies have suggested that insulin-like growth factor-1 (IGF-1) is altered in schizophrenia. The objective of this study was to investigate whether plasma IGF-1 levels were altered at the onset of psychiatric disorders such as schizophrenia or bipolar disorder. We focused at the first psychotic episode (FPE) and during 1-year follow-up. We also studied if IGF-1 levels were related to clinical symptoms. 50 patients and 43 healthy controls matched by age, gender and educational level were selected from the Basque Country catchment area in Spain. Plasma IGF-1 levels were measured at FPE and 1 month, 6 months and one year later. Patient symptoms were assessed at the same disease stages using the Positive and Negative Symptoms Scale (PANSS), the Global Assessment of Functioning (GAF), the Hamilton Depression Rating Scale (HDRS21) and the Young Mania Rating Scale (YMRS). A statistically significant increase in the plasma levels of IGF-1 was found in the whole cohort of patients one month after FPE compared to matched controls (219.84 ng/ml vs 164.15 ng/ml; p=0.014), as well as in schizophrenia patients alone at that stage (237.60 ng/ml vs 171.60 ng/ml; p=0.039). In turn, negative symptoms in both groups of patients were positively correlated with IGF-1 levels both at FPE (β=0.521; p<0.001) and after 1 year (β=0.659; p=0.001), being patients diagnosed with schizophrenia the main contributors to this relationship. These results indicate that there is a significant change in the plasma levels of IGF-1 at the initial stages of schizophrenia but not in bipolar disorder, and suggest that IGF-1 could have role in the pathophysiology of negative symptoms.

Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis

BackgroundCognitive impairments are seen in first psychotic episode (FEP) patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF) levels are associated with cognitive impairment in FEP patients compared with healthy controls.Methods45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment.ResultsPlasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability, immediate and delayed memory, abstract thinking and processing speed) which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ) and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores.ConclusionOur results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

Axon-to-Glia Interaction Regulates GABAA Receptor Expression in Oligodendrocytes.

Myelination requires oligodendrocyte-neuron communication, and both neurotransmitters and contact interactions are essential for this process. Oligodendrocytes are endowed with neurotransmitter receptors whose expression levels and properties may change during myelination. However, only scant information is available about the extent and timing of these changes or how they are regulated by oligodendrocyte-neuron interactions. Here, we used electrophysiology to study the expression of ionotropic GABA, glutamate, and ATP receptors in oligodendrocytes derived from the optic nerve and forebrain cultured either alone or in the presence of dorsal root ganglion neurons. We observed that oligodendrocytes from both regions responded to these transmitters at 1 day in culture. After the first day in culture, however, GABA sensitivity diminished drastically to less than 10%, while that of glutamate and ATP remained constant. In contrast, the GABA response amplitude was sustained and remained stable in oligodendrocytes cocultured with dorsal root ganglion neurons. Immunochemistry and pharmacological properties of the responses indicated that they were mediated by distinctive GABAA receptors and that in coculture with neurons, the oligodendrocytes bearing the receptors were those in direct contact with axons. These results reveal that GABAA receptor regulation in oligodendrocytes is driven by axonal cues and that GABA signaling may play a role in myelination and/or during axon-glia recognition.

Cystine/glutamate antiporter blockage induces myelin degeneration

The cystine/glutamate antiporter is a membrane transport system responsible for the uptake of extracellular cystine and release of intracellular glutamate. It is the major source of cystine in most cells, and a key regulator of extrasynaptic glutamate in the CNS. Because cystine is the limiting factor in the biosynthesis of glutathione, and glutamate is the most abundant neurotransmitter, the cystine/glutamate antiporter is a central player both in antioxidant defense and glutamatergic signaling, two events critical to brain function. However, distribution of cystine/glutamate antiporter in CNS has not been well characterized. Here, we analyzed expression of the catalytic subunit of the cystine/glutamate antiporter, xCT, by immunohistochemistry in histological sections of the forebrain and spinal cord. We detected labeling in neurons, oligodendrocytes, microglia, and oligodendrocyte precursor cells, but not in GFAP+ astrocytes. In addition, we examined xCT expression and function by qPCR and cystine uptake in primary rat cultures of CNS, detecting higher levels of antiporter expression in neurons and oligodendrocytes. Chronic inhibition of cystine/glutamate antiporter caused high toxicity to cultured oligodendrocytes. In accordance, chronic blockage of cystine/glutamate antiporter as well as glutathione depletion caused myelin disruption in organotypic cerebellar slices. Finally, mice chronically treated with sulfasalazine, a cystine/glutamate antiporter inhibitor, showed a reduction in the levels of myelin and an increase in the myelinated fiber g‐ratio. Together, these results reveal that cystine/glutamate antiporter is expressed in oligodendrocytes, where it is a key factor to the maintenance of cell homeostasis. GLIA 2016. GLIA 2016;64:1381–1395

P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis

Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro‐inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin‐induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti‐inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE. Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage.