One of the most detailed 3D images of the synapse, the crucial junction where neurons exchange chemical signals, has been created by researchers. Neurodegenerative diseases like Huntington’s and schizophrenia can be better understood and studied with the assistance of these nanometer-scale models.
A team led by Steve Goldman, MD, Ph.D., co-director of the Center for Translational Neuromedicine at the University of Rochester and the University of Copenhagen, published the new study in PNAS. The findings are a significant technical accomplishment that enables researchers to examine the various cells that converge at individual synapses in unprecedented depth.
Abdellatif Benraiss, Ph.D., a research associate professor in the Center for Translational Neuromedicine and co-author of the study, stated, “It is one thing to understand the structure of the synapse from the literature, but it is another to see the precise geometry of interactions between individual cells with your own eyes.” A relatively new field, the ability to measure these extremely small environments has the potential to improve our understanding of a number of synaptic dysfunction-related neurodegenerative and neuropsychiatric disorders.”
“It’s one thing to read about the structure of the synapse; it’s quite another to see the precise geometry of interactions between individual cells with your own eyes,”
Abdellatif Benraiss, Ph.D., a research associate professor in the Center for Translational Neuromedicine.
The new method was used by the researchers to compare healthy mice’s brains to those of mice with the Huntington’s disease mutation. Goldman’s lab has previously demonstrated that dysfunctional astrocytes are crucial to the disease. Astrocytes, which contribute to the proper chemical environment at the synapse, are members of the glia family of support cells in the brain.
The synapses that involve medium-spiny motor neurons were the focus of the research. Huntington’s disease is characterized by the progressive loss of these cells. The first step for the researchers was to locate synapses concealed within the tangle of three distinct cells that converge at the site: the axon from a distant neuron that is presynaptic; its target, a spiny motor neuron in the post-synaptic medium; and an adjacent astrocyte’s fiber processes.
The researchers used viruses to give distinct fluorescent tags to the axons, motor neurons, and astrocytes in order to accomplish this. After that, they removed the brains, imaged the areas of interest with multiphoton microscopy, and used infrared branding, which uses lasers to create reference points in the brain tissue. This allowed the researchers to move the cells of interest later.
The team then used a serial block-face scanning electron microscope at the University of Copenhagen to examine the brain tissue. This microscope was designed to study the smallest brain structures. The device creates 3D, nanometer-scale models of the labeled cells and their interactions at the synapse by serially removing and imaging ultrathin slices of brain tissue.
“The models uncover the calculation and primary connections among astrocytes and their cooperating neurotransmitters, which is significant in light of the fact that these cells should collaborate in a particular way at the neurotransmitter level,” said Carlos Benitez Villanueva, Ph.D., senior partner in Place for Translational Neuromedicine and first creator of the review. “We can measure and describe the geometry of the synaptic environment in relation to glial disease using this method.”
The researchers found that astrocytic processes formed a strong bond with the space around the disk-shaped synapse in the healthy mice’s brains. In contrast, Huntington’s mouse astrocytes failed to invest or sequester the synapse as effectively, leaving large gaps. Chemicals that regulate cell-to-cell communication, potassium and glutamate, can leak from the synapse due to this structural flaw, potentially interfering with normal communication.
Other conditions, such as schizophrenia, amyotrophic lateral sclerosis, and frontotemporal dementias, have been linked to astrocyte dysfunction. The researchers think that using this method, we could learn a lot more about the exact structural basis of those diseases. They specifically mention that this method could be used to evaluate the efficacy of cell replacement strategies for treating these diseases, which replace diseased glial cells with healthy ones.
Extra co-creators incorporate Hans Stephensen and Jon Sporring with the College of Copenhagen and Rajmund Mokso with Lund College in Sweden.
More information: Carlos Benitez Villanueva et al, Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington’s disease, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2210719120
