Nuclear GAPDH in cortical microglia mediates stress-induced cognitive inflexibility

• Published in: bioRxiv
• Main Authors: Ramos, Adirana, Ishizuka, Koko, Ho Namkung, Hayes, Lindsay N, Saito, Atsushi, Hayashida, Arisa, Srivastava, Rupali, Elkins, Noah, Palen, Trexy, Carloni, Elisa, Tsujimura, Tsuyoshi, Coleman Calva, Ikemoto, Satoshi, Rais, Rana, Slusher, Barbara S, Niwa, Minae, Saitoh, Toshiaki, Takimoto, Eiki, Sawa, Akira
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.09.2022
• Subjects: Cognitive ability; Glyceraldehyde; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; Microglia
• DOI: 10.1101/2022.06.21.497065

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute 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. Furthermore, hyperactivation of the prelimbic layer 5 excitatory neurons, which are known to be a neuronal substrate of cognitive inflexibility, was also normalized by the pharmacological and microglia-specific genetic interventions. The RR compound may offer a mechanism-driven, translational opportunity against stress-induced cognitive inflexibility. 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. Competing Interest Statement The authors have declared no competing interest. Footnotes * The manuscript has been updated.