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Updated: Jun 28, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility
Adriana Ramos1, Koko Ishizuka2, Arisa Hayashida2,3
1Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.
Insights
Stress activates a molecular pathway in microglia, causing cognitive inflexibility. Blocking this nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade in microglia reversed these cognitive deficits in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Stress Research
Background:
- Stress-induced cognitive inflexibility impairs adaptive behavior.
- Microglia, the brain's immune cells, are increasingly implicated in neurological disorders.
- The prelimbic cortex is a key region involved in cognitive control and decision-making.
Purpose of the Study:
- To elucidate the molecular mechanism underlying stress-induced cognitive inflexibility.
- To investigate the role of microglia in the prelimbic cortex in this process.
- To identify potential therapeutic targets for stress-related cognitive impairments.
Main Methods:
- Utilized a mouse model exhibiting stress-induced deficits in rule-shifting tasks.
- Investigated the activation of the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade in microglia.
- Employed pharmacological (RR compound) and genetic interventions targeting the N-GAPDH cascade.
- Assessed microglial High-Mobility Group Box (HMGB) secretion and neuronal activity in the prelimbic cortex.
Main Results:
- Subacute cellular stress activated the N-GAPDH cascade specifically in microglia within the prelimbic cortex.
- Pharmacological and genetic blockade of N-GAPDH cascade normalized cognitive deficits.
- Elevated microglial HMGB secretion led to hyperactivation of prelimbic layer 5 excitatory neurons.
- Interventions targeting N-GAPDH normalized both HMGB signaling and neuronal hyperactivation.
Conclusions:
- Cortical microglia and their interaction with neurons play a critical role in stress-induced cognitive inflexibility.
- The N-GAPDH cascade in microglia is a key molecular mediator of stress-induced cognitive alterations.
- Targeting microglial N-GAPDH offers a potential therapeutic strategy for cognitive dysfunction caused by stress.
