Impairments in Brain-Derived Neurotrophic Factor-Induced Glutamate Release in Cultured Cortical Neurons Derived from Rats with Intrauterine Growth Retardation: Possible Involvement of Suppression of TrkB/Phospholipase C-γ Activation

Abstract

Low birth weight due to intrauterine growth retardation (IUGR) is suggested to be a risk factor for various psychiatric disorders such as schizophrenia. It has been reported that developmental cortical dysfunction and neurocognitive deficits are observed in individuals with IUGR, however, the underlying molecular mechanisms have yet to be elucidated. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with schizophrenia and play a role in cortical development. We previously demonstrated that BDNF induced glutamate release through activation of the TrkB/phospholipase C-γ (PLC-γ) pathway in developing cultured cortical neurons, and that, using a rat model for IUGR caused by maternal administration of thromboxane A2, cortical levels of TrkB were significantly reduced in IUGR rats at birth. These studies prompted us to hypothesize that TrkB reduction in IUGR cortex led to impairment of BDNF-dependent glutamatergic neurotransmission. In the present study, we found that BDNF-induced glutamate release was strongly impaired in cultured IUGR cortical neurons where TrkB reduction was maintained. Impairment of BDNF-induced glutamate release in IUGR neurons was ameliorated by transfection of human TrkB (hTrkB). Although BDNF-stimulated phosphorylation of TrkB and of PLC-γ was decreased in IUGR neurons, the hTrkB transfection recovered the deficits in their phosphorylation. These results suggest that TrkB reduction causes impairment of BDNF-stimulated glutamatergic function via suppression of TrkB/PLC-γ activation in IUGR cortical neurons. Our findings provide molecular insights into how IUGR links to downregulation of BDNF function in the cortex, which might be involved in the development of IUGR-related diseases such as schizophrenia.

Electroacupuncture ameliorate learning and memory by improving N-acetylaspartate and glutamate metabolism in APP/PS1 mice

“…Study had shown that reduced of BDNF mRNA could lead to similarly a low level of NAA, and it is closely related to age-dependent cognitive behavioral decline [ 33 ]. In addition, BDNF induced Glu release through activation of the TrkB/phospholipase C-γ (PLC-γ) pathway [ 34 – 36 ]. It indicates that the PLC-γ pathway which activated by the BDNF-TrkB signal is necessary to stimulate Glu release.…”

Untargeted metabolomics analysis of the hippocampus and cerebral cortex identified the neuroprotective mechanisms of Bushen Tiansui formula in an aβ25-35-induced rat model of Alzheimer’s disease

“…Accumulating evidence also demonstrates that BDNF exhibits a protective role against AD pathogenesis ( Colucci-D'Amato et al, 2020 ; de Pins et al, 2019 ; Liao et al, 2021 ). BDNF has also been shown to enhance the release of neurotransmitters, including glutamate, via various different pathways ( Jovanovic et al, 2000 ; Leal et al, 2014 ; Numakawa et al, 2014 ). In our previous study, we found that the levels of BDNF were decreased in the hippocampus of AD rats but increased following treatment with BSTSF ( Sheng et al, 2020 ).…”

Phosphoinositide-Specific Phospholipases C in Psychiatric Diseases and Suicide

“…The most important gene in this aspect is the brain-derived neurotrophic factor (BPDNF), which has been studied in suicide, as well as in schizophrenia. Interestingly, BPDNF and its receptor TrkB induce glutamate release through activation of a pathway involving PLC isoforms in developing cultured cortical neurons [101].…”