Brain‐derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons

Abstract

Regulation of gene expression via brain-derived neurotrophic factor (BDNF) is critical to the development of the nervous system and may well underlie cognitive performance throughout life. We now describe a mechanism by which BDNF can exert its effects on postsynaptic receptor populations that may have relevance to both the normal and diseased brain where BDNF levels either rise or fall in association with changes in excitatory neurotransmission. Increased levels of NMDA receptors (NMDARs) occur in rat cortical neurons via synthesis of new NMDA receptor 1 (NR1) subunits. The majority of synthesis is controlled by binding of cAMP response element binding protein (CREB) and early growth response factor 3 (Egr3) to the core NR1 promoter (NR1-p) region. BDNF-mediated NR1 transcription depends upon induction of the mitogen-activated protein kinase (MAPK) pathway through activation of the TrK-B receptor. Taken together with the fact that NMDAR activation stimulates BDNF synthesis, our results uncover a feed-forward gene regulatory network that may enhance excitatory neurotransmission to change neuronal behavior over time.

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

“…Expression of PIP4K2A mRNA was also reported to be significantly increased in lymphocyte cell lines derived from schizophrenia patients (Saggers-Gray et al, 2011). Early Growth Response3 (EGR3) is an early gene transcription factor, expressed throughout the brain (Beckmann and Wilce, 1997), playing an important role in neuronal development, synaptic plasticity, learning and memory processes (O’Donovan et al, 1999) It is also involved in the regulation of NMDA receptor levels in cortical neurons (Kim et al, 2012a) and various cognitive processes like learning and memory (Poirier et al, 2008). EGR3 transcript is known to be down regulated in the prefrontal cortex of SZ patients (Yamada et al, 2007).…”

Diabetic neuropathic pain: Physiopathology and treatment

“…Moreover, spinal NMethylDaspartate (NMDA) receptor expression is augmented in this condition [98] , generating increased and more frequent excitatory post synaptic currents in the lamina Ⅱ [97] . Additionally, it has been described that cAMP response element binding protein signaling, which directly regulates NMDA receptors activity [99] is enhanced in DNP [98,100] . Thus, it is plausible that augmented NMDA expression and glutamate release might contribute to spinal cord hyperactivity.…”

Androgen Modulation of Hippocampal Structure and Function

“…The effects of BDNF may be subject to local regulation at the receptor level and may include both positive and negative effects, depending on factors such as the relative expression of full-length and truncated trk-B receptors, as well as levels of other neuropeptides and neurotransmitters (reviewed in Scharfman and MacLusky 2014a). BDNF powerfully regulates the expression of NMDA receptor subunits in the hippocampus, potentially affecting both glutamate sensitivity (Kim and others 2012; Martin and Finsterwald 2011) and spine density (Murphy and others 2014; Woolley and McEwen 1994). …”