Homer1 gene plays a critical role in shaping attention

Attention disorders such as ADHD involve a breakdown in our ability to separate signal from noise. The brain is constantly bombarded with information, and focus depends on its ability to filter out distractions and detect what matters. Stimulant medications improve attention by boosting activity in circuits known to govern attention, such as the prefrontal cortex. But a new study reveals a surprising alternative: reduce background activity as a way of turning down extraneous noise. 

In a paper published in Nature Neuroscience, researchers show that the Homer1 gene plays a critical role in shaping attention in just that way. Mice with lower levels of two specific versions of the gene enjoyed quieter brain activity and improved ability to focus. The findings may be the first steps toward a novel therapeutic approach to calming the mind, with implications for ADHD as well as related disorders characterized by early sensory disturbances already linked to Homer1, such as autism and schizophrenia. 

"The gene we found has a striking effect on attention and is relevant to humans," says Priya Rajasethupathy, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition at Rockefeller. 

A role for Homer1 

When researchers set out to study the genetics of attention, they did not expect to land on Homer1. Though the gene is well known to scientists for its role in neurotransmission-and many interacting proteins of Homer1 have shown up in human genetic studies of attention disorders-there were no previous indications that Homer1 itself might be steering the bus. 

So the team began by scanning the genomes of nearly 200 mice outbred from eight different parental lines, including some with wild ancestry, to mimic the genetic diversity found in human populations. This unusually broad variation made it possible to spot genetic effects that might otherwise be missed. "It was a Herculean effort, and really novel for the field," says Rajasethupathy, who credits PhD student Zachary Gershon for pulling it off. 

Using this approach, they ultimately narrowed in on their observation that high-performing mice had far lower levels of Homer1 in the prefrontal cortex, the brain's attention hub. This gene was found within a genetic locus that accounted for almost 20 percent of the variation in attention across the mice-"a huge effect," Rajasethupathy says. "Even accounting for any overestimation here of the size of this effect, which can happy for many reasons, that's a remarkable number. Most of the time, you're lucky if you find a gene that affects even 1 percent of a trait." 

Digging deeper, they showed that specifically the versions of Homer1 known as Homer1a and Ania3 were causing the difference. Mice that performed well on attention tasks had naturally lower levels of these versions, but not others, in their prefrontal cortex. Subsequent experiments showed that dialing down these versions in adolescent mice during a narrow developmental window led to striking improvements. The mice became faster, more accurate, and less distractible across multiple behavioral tests. The same manipulation in adult mice, however, had no effect, demonstrating that Homer1's influence appears to be locked into a critical early-life period. 

The biggest surprise, however, came when the team examined what Homer1 was doing to the brain, mechanistically. They found that reducing Homer1 in prefrontal cortex neurons caused those cells to upregulate GABA receptors-the molecular brakes of the nervous system. This shift created a quieter baseline and more focused bursts of activity when cues appeared: instead of firing indiscriminately, neurons conserved their activity for moments that mattered, enabling more accurate responses. 

"We were sure that the more attentive mice would have more activity in the prefrontal cortex, not less," Rajasethupathy says. "But it made some sense. Attention is, in part, about blocking everything else out." 

A prescription for mindfulness? 

The results were less surprising to Gershon, who lives with ADHD himself. "It's part of my story," he says, "and one of the inspirations for me wanting to apply genetic mapping to attention." 

Gershon was actually the first in the lab to notice that reducing Homer1 was improving focus by reducing distractions. To him, it made perfect sense. "Deep breathing, mindfulness, meditation, calming the nervous system-people consistently report better focus following these activities," he says. 

Existing therapies for attention disorders amplify excitatory signals in prefrontal circuits with stimulant medications. But these new findings point toward a potential pathway for a novel kind of ADHD medication that could calm rather than stimulate. And the fact that studies have linked Homer1 and its interacting proteins to ADHD, schizophrenia, and autism suggests that further study of this gene may provide new frameworks for thinking about a number of neurodevelopmental disorders. 

Future work from the Rajasethupathy lab will endeavor to better understand the genetics of attention, with an eye toward therapies that could result in precise molecular targeting of Homer1 levels. 

There is a splice site in Homer1 that can be pharmacologically targeted, which may be an ideal way to help dial the knob on brain signal-to-noise levels. This offers a tangible path toward creating a medication that has a similar quieting effect as meditation." 

Priya Rajasethupathy, head of the Skoler Horbach Family Laboratory of Neural Dynamics and Cognition at Rockefeller