Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development
Erica Tagliatti1, Genni Desiato2, Sara Mancinelli3
1IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, 20089 Milan, Italy; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, UK.
Abstract:
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
Insights
Triggering receptor expressed on myeloid cells 2 (Trem2) impacts neuronal development by regulating energy metabolism. Loss of Trem2 impairs developing hippocampal neurons, affecting their maturation and mitochondrial function.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (Trem2) is crucial for microglia function and linked to neurodegenerative diseases.
- Trem2's role in neuronal development, particularly in shaping neuron bioenergetics, is not well understood.
Purpose of the Study:
- To investigate the role of Trem2 in regulating the bioenergetic profile and development of hippocampal pyramidal neurons.
- To determine if Trem2 influences neuronal maturation and mitochondrial function during development.
Main Methods:
- Analysis of Trem2's impact on neuronal metabolism and mitochondrial integrity in developing hippocampal neurons.
- Transcriptional profiling of hippocampal neurons to identify altered gene signatures related to metabolism and mitochondria.
- Assessment of neuronal maturation and organelle ultrastructure in the absence of Trem2.
Main Results:
- Absence of Trem2 led to compromised energetic metabolism, reduced mitochondrial mass, and abnormal organelle ultrastructure in developing CA1 hippocampal neurons.
- Transcriptional analysis revealed pervasive alterations in metabolic, oxidative phosphorylation, and mitochondrial gene expression in neonatal hippocampal neurons lacking Trem2.
- A delay in the maturation of CA1 neurons was observed in Trem2-deficient conditions.
Conclusions:
- Trem2 plays a critical role in controlling the bioenergetic fitness of developing pyramidal neurons in a region-specific manner.
- Trem2 regulates neuronal development by influencing metabolic processes and mitochondrial function within neurons, particularly in the CA1 hippocampal subfield.
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