- The group led by researchers Ana I. Rojo and Antonio Cuadrado describe how the transcription factor NRF2 modulates the density of hippocampal synapses and their lipid composition
A team from the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM, CSIC-UAM), led by Drs. Ana Isabel Rojo and Antonio Cuadrado, in collaboration with Dr. Cláudia G Almeida (Universidade NOVA de Lisboa), has published a paper in the journal Redox Biology on the role of the transcription factor NRF2 in modulating synaptic contacts and regulating the synaptic lipidome in the hippocampus.
“Previous studies by the laboratory had suggested that NRF2 could be modulating synaptic connections in the hippocampus,” explains Daniel Carnicero, lead author of this paper, “but its role as a modulator of the synaptic lipidome had never been explored, nor had the effect of ether-linked lipids on synapses been described.”
The results of this study showed that the absence of the transcription factor NRF2, regarded as the master regulator of cellular homeostasis, caused a decrease in the number of glutamatergic synaptic contacts in both primary neurons and murine hippocampi. Furthermore, this loss of glutamatergic contacts was correlated with a variation in the lipid composition of the hippocampus and its synaptic compartment in particular.
It is noteworthy that, among all the species that were increased in the null brains for this transcription factor, the researchers found several glycerophospholipids linked by an ether bond. Given the scarcity of information about the effects of this type of chemical bond on synaptic transmission, the researchers decided to explore their possible contribution to synapses, thus establishing for the first time a neuronal model in which the lipid composition of the synapse could be modulated.
This work represents an advance in our understanding of the role of NRF2 in the brain and the functions of ether-linked glycerophospholipids, opening the door to further exploration of the relevance of lipid composition in neurotransmission processes.
Daniel Carnicero-Senabre, Mariana A. Barata, José Jiménez-Villegas, Claudia Guimas Almeida, Antonio Cuadrado, and Ana I. Rojo. NRF2 deficiency is associated with synaptic alterations and ether-linked phospholipid imbalance in the hippocampus. Redox Biology. https://doi.org/10.1016/j.redox.2025.103853