Abstract
Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB−TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB−TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB−TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses.
Highlights
The trkB − TK+ mRNA signal was evident in layers II–VI of the gray matter, and while it was more homogenously expressed across layers than brain-derived neurotrophic factor (BDNF) there was a band of increased intensity in the middle cortical layers and this band was most prominent in DLPFC and anterior cingulate cortex (ACC) (Figure 1)
We show a significant reduction in the expression of BDNF mRNA, in deeper cortical layers and predominantly in schizophrenia in most cortical areas examined
BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia, in layer VI of ACC in schizophrenia and MDD and in layer VI of inferior temporal gyrus (ITG) in schizophrenia, bipolar disorder (BPD) and MDD
Summary
Schizophrenia is a psychiatric disorder characterized by a variety of symptoms including hallucinations, social withdrawal, attention deficits and working memory impairments.[1,2] many of the symptoms that occur in schizophrenia are present in affective disorders.[3,4] This broad range of symptoms that manifest in the major mental illnesses is likely to result from shared abnormalities that occur across different neocortical regions, and some diagnostically distinct cortical abnormalities, in associative and limbic areas (such as the dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC).[5,6,7,8] The neurotrophic factor brain-derived neurotrophic factor (BDNF), along with its fulllength receptor trkB − TK+, regulates synaptic transmission and plasticity in the brain[9] and are important for normal cognitive functions and are implicated in the pathophysiology of schizophrenia and mood disorders. BDNF mRNA and protein are decreased in DLPFC in schizophrenia[10,11,12,13,14] and in DLPFC, ACC15,16 and hippocampus in mood disorders.[17,18] TrkB − TK+ mRNA abnormalities have been described in the DLPFC,[19,20] ACC21 and hippocampus[17] in schizophrenia and in DLPFC, ACC16 and entorhinal cortex of mood disorders.[17] Fulllength TrkB protein levels are decreased in DLPFC in schizophrenia,[20] and in the cerebellum in bipolar disorder (BPD).[22] Several studies have shown BDNF and TrkB mRNA and protein levels decreased in the DLPFC and hippocampus of depressed suicide victims.[23,24,25,26] These studies to date, while primarily focusing on the DLPFC and hippocampal regions, suggest that the abnormalities in BDNF and trkB − TK+ may be widespread across multiple brain areas; it is possible that neurotrophin abnormalities may vary across cortical regions responsible for different aspects of cognition, emotion and behavior and may differentiate diagnostic categories as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM). It is apparent that many patients with mental illness do not always fit neatly into a DSM category but display features, both genetic, molecular and symptomatic, that overlap; it is becoming increasing important to understand how the neuropathological changes in the brain of these patients may reflect both the common and different biological and symptomatic features of the disorders
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