Neuronal activity‐dependent local activation of dendritic unfolded protein response promotes expression of brain‐derived neurotrophic factor in cell soma

Abstract

Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity-and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation.Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box-binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity-and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Keywords: BDNF, dendrite, endoplasmic reticulum stress, IRE1, unfolded protein response, XBP1. Abbreviations used: ATF6, activating transcription factor 6; BDNF, brain-derived neurotrophic factor; BiP, binding immunoglobulin protein; bp, base pair; cAMP, cyclic adenosine monophosphate; ChIP, chromatin immunoprecipitation; CNS, central nervous system; CREB, cAMP response element-binding protein; eIF2a, a subunit of eukaryotic initiation factor 2; ERAD, ER-associated degradation; ER, endoplasmic reticulum; GFP, green fluorescence protein; GluR, glutamate receptor; IRE1, inositol requiring 1; LTP, long-term potentiation; MAP2, microtubule-associated protein 2; p38 MAPK, p38 mitogen activated protein kinase; PERK, protein kinase R-like ER kinase; PKA, protein kinase A; PSD95, postsynaptic density protein 95; ROCKII, Rhoassociated protein kinase II; S6K1, ribosomal protein S6 kinase 1; TrkB, tropomyosin-related kinase B; UPRE, unfolded protein response element; UPR, unfolded protein response; XBP1, x-box-binding protein 1.

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

“…In addition to controlling BDNF expression, XBP1 also initiates a positive feedback loop in which BDNF increases XBP1 mRNA splicing through the activation of IRE1 . A recent report identified the signaling event engaging IRE1 downstream of the BDNF receptor as phosphorylation by protein kinase A, also validating the role of XBP1s in the autoamplifying loop of BDNF to drive its own expression . Another study confirmed the effects of XBP1 on neuronal plasticity and applied these findings to a model of AD.…”

Control of mammalian brain ageing by the unfolded protein response transcription factor XBP1

“…5e and Table S4), similar to the findings obtained in Tg XBP1s animals. We also detected important changes in proteins related to extracellular matrix, suggesting an impact to secretory pathway proteostasis (Table S4) Importantly, accumulating evidence suggest that UPR mediators, and more specifically XBP1, have alternative functions in the nervous system by controlling synaptic plasticity 24 and dendritogenesis 25,26 . Importantly, the appearance of senescent cells in brain function was (Table S2, Table S3 and Table S4).…”

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders

“…XBP1s also upregulates brain-derived neurotrophic factor (BDNF) that is a major factor involved in synaptic plasticity in health and disease. Activation of Protein kinase A (PKA) via cyclic AMP by different agents in the brain can in turn influence IRE1α (Saito et al, 2018 ). Inhibition of IRE1α ameliorated the social behavior deficits, a commonly observed trait in some neuropsychiatric disorders (Crider et al, 2018 ).…”

“…Amongst the genes, BDNF was identified as a key transcriptional target of XBP1s (Martínez et al, 2016 ). Neuronal activity induced by glutamate increases IRE1α/XBP1 signaling in dendrites with an enhanced BDNF transcription, whilst the addition of recombinant BDNF treatment upregulated IRE1α/XBP1 (Saito et al, 2018 ). Protein Kinase A (PKA) was shown to be an important mediator in this process.…”