Home > Publications Database > Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling. > print

001     282582
005     20251218103444.0
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082 _ _ |a 570
100 1 _ |a Oberländer, Kristin
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245 _ _ |a Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.
260 _ _ |a London
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|b Springer Nature
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520 _ _ |a Synaptic 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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650 _ 7 |a Brain-Derived Neurotrophic Factor
|2 NLM Chemicals
650 _ 7 |a Receptors, N-Methyl-D-Aspartate
|2 NLM Chemicals
650 _ 7 |a Homer Scaffolding Proteins
|2 NLM Chemicals
650 _ 7 |a Homer1 protein, mouse
|2 NLM Chemicals
650 _ 7 |a Bdnf protein, mouse
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Brain-Derived Neurotrophic Factor: genetics
|2 MeSH
650 _ 2 |a Brain-Derived Neurotrophic Factor: metabolism
|2 MeSH
650 _ 2 |a Receptors, N-Methyl-D-Aspartate: metabolism
|2 MeSH
650 _ 2 |a Receptors, N-Methyl-D-Aspartate: genetics
|2 MeSH
650 _ 2 |a Homer Scaffolding Proteins: genetics
|2 MeSH
650 _ 2 |a Homer Scaffolding Proteins: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Transcriptome
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: metabolism
|2 MeSH
650 _ 2 |a Neurodegenerative Diseases: genetics
|2 MeSH
650 _ 2 |a Hippocampus: metabolism
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Huntington Disease: genetics
|2 MeSH
650 _ 2 |a Huntington Disease: metabolism
|2 MeSH
650 _ 2 |a Gene Expression Regulation
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
700 1 _ |a Pruunsild, Priit
|0 0000-0001-6823-6683
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700 1 _ |a Koch, Philipp
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700 1 _ |a Yan, Jing
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700 1 _ |a Szafranski, Karol
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700 1 _ |a Bading, Hilmar
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773 _ _ |a 10.1038/s42003-025-09074-9
|g Vol. 8, no. 1, p. 1743
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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