Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25: 372-383
Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.
"Interneurons express tropomyosin related kinase (TrkB) and require pyramidal neuron synthesized brain derived neurotrophic factor (BDNF) for differentiation and maturation (Glorioso et al., 2006). Reductions in gene expression and protein level of both BDNF and its cognate tyrosine kinase receptor, TrkB, have been identified in the DLPFC of individuals with schizophrenia and these reductions have been proposed to contribute to the reduced health of interneurons in schizophrenia (Weickert et al., 2003, 2005; Hashimoto et al., 2005; Lewis et al., 2005; Wong et al., 2010; Ray et al., 2014). A recent meta-analysis has also shown that BDNF blood levels are reduced in both medicated and drugnaïve patients with schizophrenia (Green et al., 2011). "
"Therefore, our GABA-Aα5 and GABA-Aε findings lend further support to the notion that altered tonic inhibition by GABA may contribute to the pathophysiology of schizophrenia (Maldonado-Aviles et al., 2009). Reduced GAD67 expression is a consistent finding in schizophrenia (Akbarian et al., 1995; Guidotti et al., 2000; Volk et al., 2000; Woo et al., 2004; Hashimoto et al., 2005, 2008a,b; Thompson et al., 2009; Duncan et al., 2010; Curley et al., 2011; Kimoto et al., 2014); however, we observed increased GAD67 expression in the ACC of the female schizophrenia group. It is possible that this difference may be due to medication because we observed that the expression of GAD67 was significantly higher in patients who were on medication compared with those who were off medication (Fig. 2; Table 3). "
"Beyond that, post-mortem findings displayed reduced BDNF concentrations in cortical and subcortical areas, leading to disturbed neural plasticity mediated by reduced neuronal trophic support (Takahashi et al., 2000; Durany et al., 2001; Weickert et al., 2003). In another study, BDNF expression levels and the mRNA of its receptor tyrosine kinase TrkB were found to be decreased in the prefrontal cortex of two schizophrenia cohorts (Hashimoto et al., 2005). Based on the observation that BDNF-TrkB signaling has an influence on the development of GAD67 and parvalbumin-positive GABAergic neurons (Huang et al., 1999; Cotrufo et al., 2003), the authors hypothesized that the impairments of BDNF-TrkB signaling in schizophrenia might be an upstream event contributing to the altered expression of GABA-related genes in schizophrenia (Takahashi et al., 2000). "
[Show abstract][Hide abstract] ABSTRACT: Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients.
The International Journal of Neuropsychopharmacology 10/2014; 18(4). DOI:10.1093/ijnp/pyu040 · 4.01 Impact Factor
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