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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    • "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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    • "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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