1. Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility.
- Author
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Ramos A, Ishizuka K, Hayashida A, Namkung H, Hayes LN, Srivastava R, Zhang M, Kariya T, Elkins N, Palen T, Carloni E, Tsujimura T, Calva C, Ikemoto S, Rais R, Slusher BS, Niwa M, Saito A, Saitoh T, Takimoto E, and Sawa A
- Subjects
- Animals, Mice, Male, Cerebral Cortex metabolism, Stress, Psychological metabolism, Mice, Inbred C57BL, Cognition physiology, HMGB1 Protein metabolism, Glyceraldehyde-3-Phosphate Dehydrogenases metabolism, Signal Transduction physiology, Cognitive Dysfunction metabolism, Disease Models, Animal, Cell Nucleus metabolism, Microglia metabolism, Neurons metabolism
- Abstract
We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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