Decreased BDNF, trkB-TK+ and GAD(67) mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders

Stanley Laboratory of Brain Research, Rockville, MD 20850, USA.
Journal of psychiatry & neuroscience: JPN (Impact Factor: 5.86). 05/2011; 36(3):195-203. DOI: 10.1503/jpn.100048
Source: PubMed


Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (trkB-TK+) and glutamic acid decarboxylase (GAD67) mRNA levels have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. To determine whether this reduction extends to other brain regions, we measured the expression levels of BDNF, trkB-TK+ and GAD67 mRNA in regions of the hippocampus, including the dentate gyrus (DG), cornu ammonis subfields (CA1-4), subiculum and entorhinal cortex (EC) of individuals with schizophrenia, bipolar disorder, major depression and unaffected controls.
In situ hybridization was performed on postmortem brain tissue obtained from the Stanley Foundation Consortium and analyzed using film-based quantification. Results: Analyses of covariance comparing the expression of mRNA among all groups revealed a significant decrease in BDNF mRNA in CA4 in the bipolar disorder group compared with controls (33%). We found trkB-TK+ mRNA levels to be significantly reduced in CA4 in the schizophrenia group (36%) and in layer II of the EC in the bipolar disorder and major depression groups (28%, 21%, respectively) compared with controls. In addition, GAD67 mRNA levels were reduced in patients with schizophrenia in both the DG (23%) and CA4 (60%) compared with controls. Individuals with major depression also expressed significantly less GAD67 mRNA (44%) compared with controls in CA4 of the hippocampus.
It is necessary to account for factors that influence the molecular preservation in postmortem brain tissue, including pH, postmortem interval and tissue storage time. Moreover, there are limitations to the sensitivity of the film-based method of quantification.
Our findings show abnormal BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, indicating that fundamental properties of hippocampal signalling transmission, plasticity and circuitry may be affected in individuals with these major mental illnesses.

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Available from: Maree J Webster, Sep 30, 2015
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    • "Microtubule-associated protein type 2 (MAP2) was found increased in the Ammon's horn and subiculum [76], while overall loss of somatostatin-and parvalbuminpositive interneurons has been reported [74] [77]. Decreased BDNF expression [72] [78], loss of mossy fiber synapses [79], and decreased expression of several synaptic proteins have also been described in hippocampi of patients with schizophrenia [80] [81]. Although Kraepelin in the early 1900s believed that schizophrenia had an organic cause and likely the characteristics of a degenerative process, the majority of contemporary neuropathological studies have failed to show signs of progressive features such as reactive gliosis or correlations between structural abnormalities and the length of illness [68]. "
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    ABSTRACT: Temporal lobe epilepsy (TLE) and psychosis coexist more frequently than chance would predict. In this short review, clinical and neuropathological findings of schizophrenia, TLE, and psychosis of epilepsy are described to enhance our understanding of the noncoincidental association between these conditions. In addition, psychosis of epilepsy was included for the first time in the Diagnostic and Statistical Manual of Mental Disorders (DSM), in the recently launched 5th edition, and improvement in diagnostic criteria was highlighted. Since the hippocampus has long been considered an anatomical area involved in the pathophysiology of TLE and schizophrenia, neuropathological studies of psychoses of epilepsy may contribute to our understanding of the pathophysiology of psychosis in general. The discovery of shared mechanisms and/or affected neurochemicals in TLE and schizophrenia might disclose important clues on the vulnerability of patients with TLE to psychotic symptoms and be an opportunity for new treatment development. This article is part of a Special Issue entitled “NEWroscience 2013”.
    Epilepsy & Behavior 09/2014; 38. DOI:10.1016/j.yebeh.2014.01.005 · 2.26 Impact Factor
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    • "As our patient sample included some individuals who were within the first 5 years of diagnosis, they may have been at a higher glutamate state overall, relative to a more chronically ill sample when cortical glutamate has been consistently shown to be decreased (Marsman et al. 2013). Furthermore, many of the people with schizophrenia in our study had a diagnosis of schizo-affective disorder and were receiving clozapine and/or antidepressants, which may increase BDNF levels (Pedrini et al. 2011; Thompson Ray et al. 2011; Kim et al. 2012; Martocchia et al. 2014; Mitic et al. 2014; Ray et al. 2014). We did not exclude smokers in our sample. "
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    ABSTRACT: Background: Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptogenesis and synaptic plasticity underlying learning. However, a relationship between circulating BDNF levels and brain activity during learning has not been demonstrated in humans. Reduced brain BDNF levels are found in schizophrenia and functional neuroimaging studies of probabilistic association learning in schizophrenia have demonstrated reduced activity in a neural network that includes the prefrontal and parietal cortices and the caudate nucleus. We predicted that brain activity would correlate positively with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia. Method: Twenty-five healthy adults and 17 people with schizophrenia or schizo-affective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: We found a positive correlation between circulating plasma BDNF levels and brain activity in the parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant diagnostic difference. Conclusions: This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning, suggesting that plasma BDNF levels may reflect learning-related brain activity in healthy humans. The lack of relationship between plasma BDNF and task-related brain activity in patients suggests that circulating blood BDNF may not be indicative of learning-dependent brain activity in schizophrenia.
    Psychological Medicine 08/2014; 45(04). DOI:10.1017/S0033291714001925 · 5.94 Impact Factor
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    • "There are scarce reports on hippocampal NT receptors expression in schizophrenia and mood disorders, showing unaltered, decreased and increased levels [31,56,57]. Since our series refers to psychiatric states comorbid with epilepsy, our discussion will focus mainly in NT receptors expression considering whenever possible evidences found in epilepsy. "
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    ABSTRACT: Epilepsy and psychiatric comorbidities are frequently associated, but their common biological substrate is unknown. We have previously reported altered structural elements and neurotrophins (NTs) expression in mesial temporal lobe epilepsy (MTLE) patients with psychiatric comorbidities. NTs receptors can regulate neurotransmission and promote neuroplasticity, being important candidates in the regulation and manifestation of psychopatological states and seizure-related events. MTLE hippocampi of subjects without psychiatric history, MTLE¿+¿major depression, MTLE¿+¿interictal psychosis derived from epilepsy surgery, and control necropsies were investigated for p75NTR, TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75NTR, decreased TrkA, unaltered TrkC, and complex alterations involving TrkB expression were seen in MTLE groups. Increased TrkB expression in patients without complete seizure remission and in those with secondarily generalized seizures was seen. Decreased p75NTR expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75NTR/TrkB ratios were lower than in MTLE without psychiatric comorbidities. Our results provide evidence of alterations in expression of NTs receptors in the epileptogenic hippocampus that are differentially modulated in presence of psychiatric comorbidities. As already explored in animal models, even in chronic human MTLE increased TrkB expression, among other NT receptors alterations, may play a major role in seizure type, frequency and surgery outcome.
    07/2014; 2(1):81. DOI:10.1186/PREACCEPT-5185032491303487
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