Summary: Astrocytes can alter neurons to drive behaviors associated with ADHD. Researchers believe astrocytes may be used to develop targeted treatments for behavioral deficits associated with a range of mental illnesses.
A new UCLA study suggests that brain cells called astrocytes, previously thought to provide mainly nourishment and housekeeping functions for neurons, may play a key role in the regulation of attention deficit disorder and hyperactivity.
Attention deficit hyperactivity disorder, or ADHD, is estimated to affect about 7 percent of children and adults in the U.S. Although the disorder has been the subject of much research, as well as scientific and public discussion, in recent years, the causes for the rise in ADHD are still unclear.
The research, published in the journal Cell, was led by Baljit Khakh, a professor of physiology and neurobiology at the David Geffen School of Medicine at UCLA. A central aim of Khakh’s lab has been to understand more about how astrocytes affect and regulate neural networks.
“Unmasking how astrocytes contribute to brain function is one of the most important open questions in neuroscience,” Khakh said.
“We have made some progress, but our earlier work did not tell us how increased astrocyte calcium signaling — a common method of communication used by astrocytes and neurons — would affect neurons and the neural circuits in which they reside. We set out to attack this problem.”
Last year, his team showed that astrocytes’ regulation of neurons in a part of the brain called the striatum influences repetitive behaviors like those seen in obsessive-compulsive disorder, or OCD. The new study made a chance discovery regarding how astrocyte signaling in the striatum — which plays roles in motor movement, cognition and decision-making — also affects ADHD-like behaviors. Earlier human brain imaging studies had suggested that the striatum is involved in attention deficit hyperactivity disorder, among a number of other psychiatric disorders.
In the new study, the team used a method that increases astrocyte calcium signals in mice. Astrocytes in the striatum of adult mice were “infected” with a particular kind of receptor. The team administered a compound to stimulate the receptor, which ultimately boosted the astrocytes’ calcium levels.
To observe how this change affected the animals’ behavior, each animal was placed in an empty arena and allowed to explore. The treated mice were more active and traveled significantly greater distances than the untreated mice.
Although the authors first attributed the increased activity to changes in motor control, the treated mice performed just as well as untreated animals in motor challenges. When the team looked more closely at the mice’s behavior, they observed that the treated animals also showed an apparent lack of attention in certain behavioral tasks.
“For a while, we wondered why the treated mice sometimes did not perform well on simple tasks,” said Jun Nagai, the study’s first author and a postdoctoral researcher in Khakh’s lab. “It turned out that they displayed disrupted attention. The mice did not pay attention to changes in ambient light levels and to novel objects, while normal mice do. We believe this may reflect attention deficit hyperactivity-like behaviors.”
Next, the team wanted to understand more about what molecular changes might be occurring to alter the neurons’ — and therefore the rodents’ — activity. Using a combination of techniques, the researchers found that the cascade of events actually begins with the release of the neurotransmitter GABA from neurons in the striatum, which leads to a rise in calcium levels in astrocytes. They showed that this calcium increase changes the expression of a gene known as Thbs1.
“The finding that we could observe psychiatric-related behaviors after astrocyte-specific signaling was triggered was somewhat unexpected,” Khakh says. “Along with work we published last year on astrocytes’ role in [obsessive compulsive disorder], our current results suggest that astrocytes can alter neurons to drive complex behavioral traits and characteristics. We suspect that ultimately this means that astrocytes could be exploited to treat behaviors associated with mental illness.”
Khakh and his team plan to continue exploring astrocytes in brain function in the coming years, including how their activity may affect other types of psychiatric disorders.
In addition to Khakh and Nagai, other study authors are Abha Rajbhandari, Mohitkumar Gangwani, Ayaka Hachisuka, Sotiris Masmanidis, Michael Fanselow and Giovanni Coppola, all of UCLA.
Funding: The study was funded by the National Institutes of Health. Khakh was also supported by the Ressler Family Foundation. Nagai was supported by postdoctoral fellowships from the Japan Society for the Promotion of Science and Uehara Memorial Foundation.
Alice Walton – UCLA
The image is in the public domain.
Original Research: Closed access
“Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue”. Baljit Khakh et al. Cell. doi:10.1016/j.cell.2019.03.019
Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue
• Striatal MSNs release GABA to activate astrocyte Gi-coupled GABA B receptors
• Astrocyte Gi pathway activation results in hyperactivity with disrupted attention
• Astrocyte Gi pathway activation increases fast synaptic excitation and MSN firing
• Behavioral and synaptic effects are due to reactivation of TSP1 in astrocytes
Hyperactivity and disturbances of attention are common behavioral disorders whose underlying cellular and neural circuit causes are not understood. We report the discovery that striatal astrocytes drive such phenotypes through a hitherto unknown synaptic mechanism. We found that striatal medium spiny neurons (MSNs) triggered astrocyte signaling via γ-aminobutyric acid B (GABA B) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acute behavioral hyperactivity and disrupted attention. Such responses also resulted in upregulation of the synaptogenic cue thrombospondin-1 (TSP1) in astrocytes, increased excitatory synapses, enhanced corticostriatal synaptic transmission, and increased MSN action potential firing in vivo. All of these changes were reversed by blocking TSP1 effects. Our data identify a form of bidirectional neuron-astrocyte communication and demonstrate that acute reactivation of a single latent astrocyte synaptogenic cue alters striatal circuits controlling behavior, revealing astrocytes and the TSP1 pathway as therapeutic targets in hyperactivity, attention deficit, and related psychiatric disorders.