Summary: Reducing tau can prevent abnormal brain activity associated with Alzheimer’s disease, autism, and epilepsy.
Source: Gladstone Institutes
With the school year well on its way, we all recognize the importance of getting students energized. However, we also know that overstimulated children can wreak havoc on a classroom, leaving a teacher trying to regain control of their group. The situation is very similar in the brain, where cells must remain active—but in an orderly manner—to carry out their many important tasks.
If too many excitatory cells (the students in this metaphor) begin firing at the same time, the overexcitation can spread through an entire neural network (the classroom), resulting in epileptic activity. So, inhibitory cells (the teachers) tamp down the excitation to maintain balance in the brain.
Now, researchers at Gladstone Institutes uncovered that reducing levels of the protein tau, which is known for its role in Alzheimer’s disease and other neurodegenerative conditions, changes excitatory and inhibitory cells in ways that make it harder for the brain to burst with overexcitation.
“Epilepsy can be associated with many brain disorders, including Alzheimer’s disease and autism,” says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and senior author of the new study published in the journal Cell Reports. “We previously showed in mouse models that reducing tau levels makes the brain more resistant to epilepsy of diverse causes, but we have puzzled about the underlying mechanisms. Our recent findings shed light onto how tau reduction affects different types of brain cells involved in creating abnormal network activity.”
It is critical to preserve a balance between the activity of excitatory and inhibitory cells for the brain to process information, appropriately control movements, and perceive things as they really are, rather than in a distorted way.
“The diseases we’re interested in have in common that they cause an excitation-inhibition imbalance in the brain,” says Mucke, who is also the Joseph B. Martin Distinguished Professor of Neuroscience and a professor of neurology at UC San Francisco.
Mucke and his team discovered that reducing levels of tau impacts both excitatory and inhibitory cells, but in different ways. They showed that excitatory neurons that lack tau don’t fire as much, whereas inhibitory neurons that lack tau are more easily stimulated to fire.
Together, these effects reduce the excitation-inhibition ratio in brain networks, counteracting diseases that cause abnormal increases in that ratio. To return to the classroom example, the neural effects of reducing tau are the equivalent of making the students less rambunctious and the teachers more effective at supervising them.
Just like calm in the classroom facilitates learning, the calming effect of tau reduction on brain networks might improve the brain’s ability to perform its functions, especially when the calm is being disrupted by disease. The insights gained in the new study could help guide the development of novel therapies that target tau as a way of reducing abnormal brain activities in a range of neurological and psychiatric diseases.
Other authors include Che-Wei Chang, Mark D. Evans, Xinxing Yu, and Gui-Qiu from Gladstone.
Funding: The work was supported by the National Institutes of Health (grant MH115679), the Ray and Dagmar Dolby Family Fund, the Tau Consortium, the Alzheimer’s Association, and an Alan Kaganov Scholarship.
Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony
Tau ablation reduces baseline activity and E/I ratio of excitatory neurons
Tau ablation preferentially increases the excitability of inhibitory neurons
Tau ablation modulates the AISs of inhibitory neurons
Reduced neuronal activity and enhanced inhibition counteract network hypersynchrony
The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios.
However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of these cells.
Tau ablation reduces the excitatory inputs to inhibitory neurons, increases the excitability of these cells, and structurally alters their axon initial segments (AISs). In primary neuronal cultures subjected to prolonged overstimulation, tau ablation diminishes the homeostatic response of AISs in inhibitory neurons, promotes inhibition, and suppresses hypersynchrony.
Together, these differential alterations in excitatory and inhibitory neurons help explain how tau reduction prevents network hypersynchrony and counteracts brain disorders causing abnormally increased E/I ratios.