Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility

Adriana Ramos; Koko Ishizuka; Arisa Hayashida; Ho Namkung; Lindsay N Hayes; Rupali Srivastava; Manling Zhang; Taro Kariya; Noah Elkins; Trexy Palen; Elisa Carloni; Tsuyoshi Tsujimura; Coleman Calva; Satoshi Ikemoto; Rana Rais; Barbara S Slusher; Minae Niwa; Atsushi Saito; Toshiaki Saitoh; Eiki Takimoto; Akira Sawa

doi:10.1038/s41380-024-02553-1

Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility

Mol Psychiatry. 2024 Apr 13. doi: 10.1038/s41380-024-02553-1. Online ahead of print.

Authors

Adriana Ramos^#¹, Koko Ishizuka^#², Arisa Hayashida^#^{2

3}, Ho Namkung^#⁴, Lindsay N Hayes¹, Rupali Srivastava², Manling Zhang⁵, Taro Kariya⁵, Noah Elkins², Trexy Palen², Elisa Carloni², Tsuyoshi Tsujimura², Coleman Calva⁶, Satoshi Ikemoto⁶, Rana Rais^{7

8}, Barbara S Slusher^{1

2

5

7

8}, Minae Niwa², Atsushi Saito¹, Toshiaki Saitoh⁹, Eiki Takimoto⁵, Akira Sawa^{10

11

12

13

14

15}

Affiliations

¹ Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Departments of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ International Collaborative Research Administration, Juntendo University, Tokyo, Japan.
⁴ Departments of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Neurocircuitry of Motivation Section, National Institute on Drug Abuse, Baltimore, MD, USA.
⁷ Departments of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Nihon Pharmaceutical University, Saitama, Japan.
¹⁰ Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. asawa1@jhmi.edu.
¹¹ Departments of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. asawa1@jhmi.edu.
¹² Departments of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. asawa1@jhmi.edu.
¹³ Departments of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. asawa1@jhmi.edu.
¹⁴ Departments of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. asawa1@jhmi.edu.
¹⁵ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. asawa1@jhmi.edu.

^# Contributed equally.

PMID: 38615102
DOI: 10.1038/s41380-024-02553-1

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.

Grants and funding

R01 MH107730/MH/NIMH NIH HHS/United States