The nuclear GAPDH-HMGB cascade in cortical microglia regulates cognitive flexibility
Ramos, A.; Ishizuka, K.; Namkung, H.; Hayes, L. N.; Saito, A.; Sengupta, A.; Srivastava, R.; Calva, C.; Hayashida, A.; Elkins, N.; Palen, T.; Carloni, E.; Tsujimura, T.; Gallego, J. A.; Robinson, D. G.; Malhotra, A. K.; Ikemoto, S.; Rais, R.; Slusher, B. S.; Niwa, M.; Saitoh, T.; Takimoto, E.; Sawa, A.
Show abstract
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.
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