Characterizing the transcription profile of microglia in a mouse model

In the central nervous system, microglia serve as the first line of defense, continually searching for pathogens and abnormalities and releasing tiny proteins called cytokines to fight infections.

Previous studies have demonstrated that microglia play a crucial role in transferring traumatic memories from short to long-term memory (fear memory consolidation) in mice that have been trained to fear a specific environment (contextual fear conditioning) and in the subsequent extinction of those memories.

Researchers from Tohoku University have now shown that the consolidation and extinction of contextual fear conditioning alter the microglial genes connected to the synapse—structures that permit neurons to communicate with one another.

This reveals the pathways connecting microglia and neuronal activity relevant to fear conditioning and suggests that microglia and neurons crosstalk via “non-immune” roles.

On August 18^th, 2022, the study was published in the journal Brain Research Bulletin.

Prior research by Dr. Zhiqian Yu, Professor Hiroaki Tomita, and their colleagues at Tohoku University’s Graduate School of Medicine demonstrated that TNF-a, a type of cytokine employed by the immune system for cell signaling, was released by the microglia of stressed mice.

TNF-a increased during the development of fear memories, whereas it decreased upon extinction. Additionally, TNF-a in the hippocampi prevents the consolidation and recall of spatial and contextual fear memories.

The scientists used microarray techniques in the microglia of mice that had undergone contextual fear conditioning, building on the findings of the prior study. They demonstrated that contextual fear conditioning alters the synapse-related genes in microglia. However, they also found that the immunological dysfunction caused by consolidating the fear memory in microglia persisted even during the process of extinction.

Gamma-aminobutyric acid (GABA) and GABAR receptors (GABAR) are the initial neurotransmitter systems to appear throughout development among the multitude of synaptic function-related genes in microglia. In neurological conditions like epilepsy and autism, the GABARB3 encodes the GABAA receptor’s β3 subunit.

Using real-time PCR and immune stain technologies, we found that GABRB3 was expressed in microglial cytoplasm and the long branching processes of the hippocampus. The mRNA and protein levels of GABRB3 changed significantly after fear memory consolidation but recovered after extinction.”

Dr Zhiqian Yu, Graduate School of Medicine, Tohoku University

The scientists also looked at the Synapsin protein family, which controls neurotransmitter release at synapses. In MG-6 cell line and primary microglia that expanded during the consolidation of fear memories but recovered following the extinction of those memories, microglial Synapsin transcription was expressed.

Under contextual fear conditions, immune-related genes decreased with no significant morphological changes, indicating a change in microglial activation states. All of this suggests that microglia-neuron communication mediates contextual fear conditioning, and it may be based on non-immune functions.”

Dr Zhiqian Yu, Graduate School of Medicine, Tohoku University