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000282582 1001_ $$0P:(DE-2719)2812835$$aOberländer, Kristin$$b0$$eFirst author$$udzne
000282582 245__ $$aInhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.
000282582 260__ $$aLondon$$bSpringer Nature$$c2025
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000282582 520__ $$aSynaptic activity-regulated gene expression supports neuroprotection, plasticity, and memory. The transcription factor CREB is central to these processes. It is activated by synaptic NMDA receptors but inactivated by excitotoxic extrasynaptic NMDAR (esNMDAR) signaling. Using primary hippocampal neurons, we modeled neurodegeneration and found that esNMDAR activation, which causes CREB shut-off and inactivation of the ERK/MAPK-ELK1/SRF pathway, extensively distorted control of synaptic activity over transcription. This resulted in the suppression of key neuroprotective genes, in particular Inhba and Bdnf, but also of genes involved in synaptic function (Homer1, Btg2, Mir132, Mir212) and transcription factor genes (Atf3, Egr1, Fos, Npas4). In a Huntington's disease (HD) mouse model, treatment with memantine or targeting the NMDAR/TRPM4 complex with FP802 restored gene expression, notably Inhba, Homer1 and Bdnf, and attenuated the decrease of the HD disease marker Ppp1r1b (DARPP-32). These findings identify esNMDAR-driven transcriptional dysregulation as a key pathomechanism in neurodegenerative disease, supporting inhibition of esNMDAR-signaling as a promising therapeutic approach.
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000282582 650_7 $$2NLM Chemicals$$aBrain-Derived Neurotrophic Factor
000282582 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000282582 650_7 $$2NLM Chemicals$$aHomer Scaffolding Proteins
000282582 650_7 $$2NLM Chemicals$$aHomer1 protein, mouse
000282582 650_7 $$2NLM Chemicals$$aBdnf protein, mouse
000282582 650_2 $$2MeSH$$aAnimals
000282582 650_2 $$2MeSH$$aBrain-Derived Neurotrophic Factor: genetics
000282582 650_2 $$2MeSH$$aBrain-Derived Neurotrophic Factor: metabolism
000282582 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000282582 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: genetics
000282582 650_2 $$2MeSH$$aHomer Scaffolding Proteins: genetics
000282582 650_2 $$2MeSH$$aHomer Scaffolding Proteins: metabolism
000282582 650_2 $$2MeSH$$aMice
000282582 650_2 $$2MeSH$$aSignal Transduction
000282582 650_2 $$2MeSH$$aTranscriptome
000282582 650_2 $$2MeSH$$aNeurodegenerative Diseases: metabolism
000282582 650_2 $$2MeSH$$aNeurodegenerative Diseases: genetics
000282582 650_2 $$2MeSH$$aHippocampus: metabolism
000282582 650_2 $$2MeSH$$aNeurons: metabolism
000282582 650_2 $$2MeSH$$aHuntington Disease: genetics
000282582 650_2 $$2MeSH$$aHuntington Disease: metabolism
000282582 650_2 $$2MeSH$$aGene Expression Regulation
000282582 650_2 $$2MeSH$$aDisease Models, Animal
000282582 650_2 $$2MeSH$$aMale
000282582 650_2 $$2MeSH$$aMice, Inbred C57BL
000282582 7001_ $$00000-0001-6823-6683$$aPruunsild, Priit$$b1
000282582 7001_ $$0P:(DE-HGF)0$$aKoch, Philipp$$b2
000282582 7001_ $$aYan, Jing$$b3
000282582 7001_ $$00000-0001-6391-1766$$aSzafranski, Karol$$b4
000282582 7001_ $$00000-0003-0258-4348$$aBading, Hilmar$$b5
000282582 773__ $$0PERI:(DE-600)2919698-X$$a10.1038/s42003-025-09074-9$$gVol. 8, no. 1, p. 1743$$n1$$p1743$$tCommunications biology$$v8$$x2399-3642$$y2025
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