| First Author | Ramos A | Year | 2024 |
| Journal | Mol Psychiatry | Volume | 29 |
| Issue | 10 | Pages | 2967-2978 |
| PubMed ID | 38615102 | Mgi Jnum | J:372949 |
| Mgi Id | MGI:8250653 | Doi | 10.1038/s41380-024-02553-1 |
| Citation | Ramos A, et al. (2024) Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility. Mol Psychiatry 29(10):2967-2978 |
| abstractText | 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. |
