Mind’s sensory processor could immediate reminiscence issues in autism | Spectrum
Short circuit: Several genes linked to autism (top) and schizophrenia (bottom) are highly expressed in the thalamus of mice and, when mutated, appear to cause memory problems.
Silencing multiple genes associated with autism or schizophrenia in the thalami of mice increases neuronal excitability there and leads to memory problems reminiscent of those in people with these disorders, shows a new study. A drug that reverses hyperexcitability increases the animals’ memory and suggests a pathway for future therapies, researchers say.
“It’s exciting to see how different genetic changes can converge on the same circuits in the brain and even on the same physiological mechanism,” said Audrey Brumback, assistant professor of neurology and pediatrics at the University of Texas at Austin, who was not involved in the research . “We are then really approaching the ultimate common path that could be a goal for treatment.”
Mice lacking the autism-related gene PTCHD1 in the thalamic reticular nucleus, a sub-region of the thalamus, are hyperactive and have attention deficits, according to a 2015 study. In the new work, the same team eliminated PTCHD1 expression and the expression of four other genes associated with either autism or schizophrenia in a different sub-region, the anterodorsal thalamus.
In all five models, the manipulated mice performed poorly in tests of long-term and working memory. These memory problems could contribute to learning disabilities in people with autism or schizophrenia, the researchers say. In three of the five models, the memory problems appeared to be due to increased excitability of the thalamic neurons.
“It’s now very clear that every phenotype or symptom you have has a specific circuit responsible,” says lead researcher Guoping Feng, Poitras professor of neuroscience at the Massachusetts Institute of Technology in Cambridge. The work was published in Neuron in June.
Scientists have long held the thalamus responsible for processing sensory information and transmitting it to the cerebral cortex. Feng’s previous work on PTCHD1 suggested that the thalamus may also play a role in cognition.
In analyzing an existing map of gene expression in the mouse brain, Feng and colleagues found that PTCHD1 and four other genes associated with autism, along with three schizophrenia risk genes, are highly expressed in the anterodorsal thalamus. They used CRISPR to block expression of each of the eight genes sequentially in that region only.
Typical mice tend to freeze when placed in a chamber that has previously received a mild foot shock – a reaction that shows they have long-term memory. However, mice lacking PTCHD1, the autism-related gene YWHAG, or one of the three schizophrenia genes struggled to make this link. When placed in a T-maze, these five mouse models also had trouble remembering a prompt that was taught to them telling them where to go.
Brain slices from mice lacking PTCHD1, YWHAG, and one of the schizophrenia genes, HERC1, also contained more excitable neurons than controls, the researchers found.
The researchers eliminated this hyperexcitability using a technique called chemogenetics, which involves genetically engineering neurons in the anterodorsal thalamus to make designer receptors for a specific drug. After treatment with the drug, the three knockdown mice no longer showed any type of memory problem.
“Now that we’ve found a mechanism of convergence for many different genes, if you can correct the convergence defect, you can use it to treat many different patients,” says Feng. “So that’s the hope, that’s the goal.”
Feng’s team separately inhibited neurons in a neighboring subregion of the thalamus, the anteroventral thalamus, and found that the animals’ long-term and working memory remained intact. However, these mice mistook a new box for one they had previously been placed in, suggesting that the sub-region is involved in memory specificity.
“You can imagine that there are people who have problems with that [types of memory] but not the other, ”says Brumback. “And the more detailed we can get into the circuits that do the things they have trouble with, rather than all the other things, the better our treatments will be.”
The team says the next step is to develop a drug that targets existing receptors only in the anterodorsal thalamus, not designer receptors. This is an important goal because current therapies numb the entire brain and cause side effects, says Sam Wang, a professor of neuroscience at Princeton University, who was not involved in the new work. “One promise of the kind of anatomically specific work they have done is to think about targeting therapies to specific brain regions for more precision.”
Researchers also need to figure out whether the results in adult mice translate to people with genetic mutations who develop brain differences as they develop, says Wang. And since other brain regions express the genes in the study, the researchers need to investigate whether these regions could also influence behavior or the anterodorsal thalamus.
“This is the tip of the iceberg,” says Wang.