Researchers at MIT have uncovered a common neural mechanism for a type of cognitive impairment seen in some people with autism spectrum disorder (ASD) and schizophrenia, even though the genetic variations that produce the impairments are different for each condition.

In a study of mice, the researchers found that certain genes that are mutated or missing in the disorders cause similar dysfunctions in a neural circuit in the thalamus. The team suggests that if it’s possible to develop drugs that target this circuit, such drugs might be used to treat people who have different disorders with common behavioral symptoms.

“This study reveals a new circuit mechanism for cognitive impairment and points to a future direction for developing new therapeutics, by dividing patients into specific groups not by their behavioral profile, but by the underlying neurobiological mechanisms,” said research lead Guoping Feng, PhD, the James W. and Patricia T. Poitras professor in brain and cognitive sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT

Feng and colleagues reported on their study in Neuron, in a paper titled, “Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models.” Dheeraj Roy, PhD, a Warren Alpert distinguished scholar and a McGovern Fellow at the Broad Institute, and Ying Zhang, PhD, a postdoc at the McGovern Institute, are the lead authors of the paper

Some neuropsychiatric disorders share similar symptoms, such as intellectual disability (ID) or attention deficits, but whether there are common causes at the neural level isn’t known, the authors wrote. “Cognitive impairments in disorders such as ASD and schizophrenia have been commonly linked to dysfunction within hippocampal and cortical circuits; however, whether converging neurobiological mechanisms underlie cognitive impairments across disorders has not been established.”

It is an issue that does have important implications, the researchers noted, because if common mechanisms can be identified, then therapeutic approaches capable of treating cognitive impairments in subsets of neuropsychiatric disorders may be feasible.

The thalamus plays a key role in cognitive tasks such as memory formation and learning. Previous studies have shown that many of the gene variants linked to brain disorders such as autism and schizophrenia are highly expressed in the thalamus, suggesting that this region of the brain may play a role in those disorders.

Feng has extensively studied one such gene, which is known as Ptchd1, and is located on the X chromosome. Research has found that loss of the gene in boys can lead to attention deficits, hyperactivity, aggression, intellectual disability, and autism spectrum disorders.

In a study published in 2016, Feng and colleagues showed that Ptchd1 exerts many of its effects in a part of the thalamus called the thalamic reticular nucleus (TRN). They demonstrated that knocking out the gene in the TRN of mice was associated with attention deficits and hyperactivity in affected animals. However, that study did not find any role for the TRN in the learning disabilities also seen in people with mutations in Ptchd1. “Our previous study in mice showed that the selective deletion of PTCHD1 from the TRN was responsible for attention deficits, hyperactivity, and sleep abnormality, but not memory deficits,” the team wrote.

For their newly reported work, the researchers decided to look elsewhere in the thalamus to try to figure out how Ptchd1 loss might affect learning and memory. Another area they identified that highly expresses Ptchd1 is called the anterodorsal (AD) thalamus, a tiny region that is involved in spatial learning and communicates closely with the hippocampus. The AD thalamus is part of the understudied anterior thalamic nuclei (ATN) complex, the authors noted, and “robust reductions in the number of ATN neurons was reported in tissue from patients, suggesting a potential role for ATN dysfunction in schizophrenia.”

Using novel techniques that allowed them to trace the connections between the AD thalamus and another brain region called the retrosplenial cortex (RSC), the researchers determined a key function of this circuit. They found that in mice, the AD-to-RSC circuit is essential for encoding fearful memories of a chamber in which they received a mild foot shock. It is also necessary for working memory, such as creating mental maps of physical spaces to help in decision making.

The researchers, in addition, found that a nearby part of the thalamus called the anteroventral (AV) thalamus also plays a role in this memory formation process: AV-to-RSC communication regulates the specificity of the encoded memory, which helps us distinguish this memory from others of similar nature. “These experiments showed that two neighboring subdivisions in the thalamus contribute differentially to memory formation, which is not what we expected,” Roy said.

Having discovered the roles of the AV and AD thalamic regions in memory formation, the team set out to investigate how this circuit is affected by loss of Ptchd1. When they knocked down (KD) expression of Ptchd1 in neurons of the AD thalamus in mice, they found a striking deficit in memory encoding, for both fearful memories and working memory.

The researchers carried out the same experiments with a series of four other genes, one (YWHAG) that represents an ASD risk gene, and three (GRIA3, CACNA1G, and HERC1) linked with schizophrenia. In all of these mice, knocking down gene expression produced the same memory impairments. “YWHAG KD mice exhibited significant CFC memory deficits,” the team noted. “Strikingly, AD-thalmus-specific KD of schizophrenia risk genes GRIA3, CACNA1G, or HERC1 all led to CFC memory deficits. Furthermore, YWHAG, GRIA3, CACNA1G, and HERC1 KD mice were impaired in the long delay working memory test, indicating that AD dysfunction induces cognitive impairments in a subset of different disease models.”

The researchers’ experiments also showed that each of these knockdowns produced hyperexcitability in neurons of the AD thalamus. The researchers say that these results are consistent with existing theories positing that learning occurs through the strengthening of synapses that occurs as a memory is formed. “The dominant theory in the field is that when an animal is learning, these neurons have to fire more, and that increase correlates with how well you learn,” Zhang commented. “Our simple idea was if a neuron fires too high at baseline, you may lack a learning-induced increase.”

The team also demonstrated that each of the genes they studied affects different ion channels that influence neurons’ firing rates. The overall effect of each mutation is an increase in neuron excitability, which leads to the same circuit-level dysfunction and behavioral symptoms.

The studies also demonstrated that that normal cognitive function in mice with these genetic mutations could be restored by artificially turning down hyperactivity in neurons of the AD thalamus. “… neuronal hyperexcitability was causally related to cognitive deficits in these KD mice, because normalization of this physiological property rescued memory deficits in all three models,” they wrote. While the approach they used, chemogenetics, is not yet approved for use in humans, it may be possible to target this circuit in other ways, the team suggested.

“This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models,” the authors concluded. They suggest that their studies “ … reveal an important link between anterior thalamic dysfunction and cognitive impairments in a subset of ASD and schizophrenia models, which may provide the foundation for developing therapeutic strategies capable of treating cognitive impairments in multiple disorders.”

The findings lend support to the idea that grouping diseases by the circuit malfunctions that underlie them may help to identify potential drug targets that could help many patients, Feng pointed out. “There are so many genetic factors and environmental factors that can contribute to a particular disease, but in the end, it has to cause some type of neuronal change that affects a circuit or a few circuits involved in this behavior,” he said. “From a therapeutic point of view, in such cases you may not want to go after individual molecules because they may be unique to a very small percentage of patients, but at a higher level, at the cellular or circuit level, patients may have more commonalities.”

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