Connection Boost: Changes in TSC2 expression increase the density of synapses from excitatory neurons (magenta) to PV interneurons (cyan, top) but not to SST interneurons (cyan, bottom).
Loss of the autism-associated gene TSC2 in parvalbumin interneurons causes these cells to form atypical synapses, according to a new study. Neural circuits built between sex cells may be particularly susceptible to developmental disorders, researchers say.
Parvalbumin (PV) and somatostatin (SST) interneurons arise from the same type of progenitor cells and share migration pathways to the neocortex, where they occupy the same layers. Beyond these similarities, however, they target different cells for connectivity and play markedly different roles within neural circuits.
A new study suggests that these different wiring patterns are due, at least in part, to differences in how the two types of interneurons express mTOR pathways associated with autism. This cell modifies the way PV interneurons (rather than SST types) receive synapses from excitatory cells.
This, in particular, suggests why PV interneuron function appears to be altered in autism-related conditions, as a previous study found, co-principal investigator, UK Oscar Mullin, professor of neuroscience at King’s College London, said. “There seems to be some degree of convergence around this cell type,” he says.
M.Mutations in TSC2 or the related gene TSC1 cause tuberous sclerosis. Proteins from both genes suppress the mTOR signaling pathway, which mediates cell growth and proliferation, and their absence results in benign tumors throughout the body, including the brain. People with tuberous sclerosis are not only more likely to be diagnosed with autism, but they also often have intellectual disability and epilepsy.
In a new study, researchers found that loss of TSC2 increased mTOR signaling in mouse brain tissue in both PV and SST interneurons, resulting in larger cells than controls. bottom. However, unlike SST interneurons, her PV interneurons that have lost her single copy of the TSC2 gene (and to a greater extent those that have lost both copies) also show altered synaptic development. I was. Connections from PV interneurons to excitatory neurons were unaffected, but excitatory cells to PV cells were denser than average.
Previous work in the group showed that postsynaptic PV interneurons depended on ERBB4 receptors to form synapses with excitable cells, and new research suggests that these receptors are regulated in two cell types. suggesting that it might explain the difference. Loss of receptor function results in hyperactivation of TSC2, blunts the mTOR pathway, and downregulates the production of specific proteins at potential synaptic sites. In contrast, receptor activation increases their expression. PV interneurons that express less of these synaptic proteins have lower densities of synapses formed by excitatory neurons, the researchers reported in his December report. chemistry.
“This suggests that protein synthesis is the cellular mechanism for altering the contribution of specific synapses within the circuit,” says Emily Osterweil, professor of molecular neuroscience at the University of Edinburgh in Scotland. says. That’s what researchers had guessed, she says, but it was difficult to explain in vivo.
And because the production of the relevant proteins occurs at the sites of these excitatory-to-inhibitory junctions, there appears to be something important about their local translation, said co-chairs. Beatriz Rico, a researcher and professor of developmental neurobiology at King’s College London, said.
That conclusion “may be a little premature,” says Eric Crane, a professor of neuroscience at New York University. The proteins Rico and her colleagues identified appear to be necessary for synaptogenesis, but this study does not show that they must be synthesized locally, he says.
S.Until the findings of this study raise interesting questions about the biology of other neurodevelopmental conditions, says Clan. It would be nice to know if it exists in animal models.
The results “also strengthen the argument that mTOR may be a convergence point for some forms of autism,” said Harvard Medical School and Boston Children’s Hospital, who were not involved in the study. Mustafa Sahin, Professor of Neurology, said:
Moving forward, the team plans to investigate whether loss of TSC2 has similar effects on synapses in human brain tissue, says Marin. “It will reassure us that we are working on something that should translate to patients. Because the ultimate goal is not just to understand biology, but to find ways to identify new treatments.” Because that’s what it is.”
Citing this article: https://doi.org/10.53053/CQBN4627
