Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia

Abstract

The brain-derived neurotrophic factor (BDNF) gene contains 4 major 5′ promoters which generate alternate transcripts. Previously, we found that pan-BDNF mRNA and protein is reduced in the dorsolateral prefrontal cortex (DLPFC) from patients with schizophrenia. In this study, we determined which of the 4 most abundant BDNF alternate transcripts (I–IX, II–IX, IV–IX and VI–IX) are altered in schizophrenia. Using a cohort from the NIMH, USA, we found that BDNF II–IX mRNA was significantly reduced in the DLPFC of patients with schizophrenia, and we replicated this finding using a second cohort from Sydney, Australia. Moreover, we show that the mature BDNF protein is reduced in the DLPFC of patients with schizophrenia, confirming and replicating our previous findings. We next determined the regional specificity of these findings by measuring BDNF transcripts in the parietal cortex and hippocampus and found no significant changes in these two brain regions. Since patients with schizophrenia are often prescribed antidepressants which can up-regulate expression of BDNF, we investigated the relationship between antidepressant treatment and BDNF transcript expression. All four BDNF transcripts were significantly up-regulated in schizophrenics patients treated with antidepressants. When we removed cases with recorded use of antidepressants, this revealed significant reductions in BDNF II–IX and IV–IX in the parietal cortex and VI–IX in the hippocampus of patients with schizophrenia. This suggests that down-regulation of at least 1/4 major BDNF transcripts occurs in various brain regions of patients with schizophrenia, particularly in the DLPFC which appears to have the most robust BDNF deficit in schizophrenia.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…While this result mirrors the decreased BDNF expression seen in patients, the Val66Met variant associated with psychosis is accompanied by less BDNF methylation in the PFC (Mill et al, 2008). Owing to the brain region-and promoter-specific nature of these effects (Wong et al, 2010), and differences in rodent and human neuroanatomy, more evidence will be required to understand the interaction between Val66Met, BDNF epigenetics, stress, and psychosis (Boulle et al, 2011). Chronic stress also interacts with the cannabinoid system to sensitize the effects of cannabinoids and shift cannabinoidmediated control of plasticity from projection neurons to GABAergic cells (Patel et al, 2009;Reich et al, 2013).…”

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

“…In rodents, differential production of Bdnf splice variants has been documented in a number of models of neurological and neuropsychiatric disease and in response to various pharmacological treatments (Dias et al, 2003;Fumagalli et al, 2012;Nair et al, 2007;Zuccato et al, 2001). In humans, misregulation of specific BDNF transcripts is associated with several brain disorders, including Huntington's disease, schizophrenia and Alzheimer's disease (Garzon et al, 2002;Wong et al, 2010;Zuccato et al, 2001). Moreover, a selective deletion of BDNF exons I-III that spares the remaining portion of the gene is sufficient to cause obesity in humans (Han et al, 2008).…”

State of Art of Serum Brain-Derived Neurotrophic Factor in Schizophrenia

“…On the other hand, Chen et al (2001) showed that there was no significant variation for mBDNF among patients with schizophrenia and those with a diagnosis of affective disorders (unipolar and bipolar disorders) and Dunham et al, (2009) detected no difference for preproBDNF (35KDa) between patients with schizophrenia and those with unipolar depression and bipolar disorder. In contrast, Wong et al (2010) found reduced truncated BDNF and preproBDNF proteins in the DLPFC of patients with schizophrenia, even if the reduction in preproBDNF protein did not achieve statistical significance. In a previous study (Carlino et al, 2011), we provided evidence of variation in serum levels of different BDNF isoforms in patients with chronic schizophrenia.…”

“…Reduced mBDNF levels were found in three studies (Karege et al, 2005;Weickert et al, 2003;Wong et al, 2010), particularly in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia compared to healthy controls. Weickert et al (2003) found that mBDNF protein levels were not associated with post-mortem interval (PMI), tissue pH, age, or storage time of the serum.…”