Call-and-response circuit tells neurons when to grow synapses

Brain cells called astrocytes play a key role in helping neurons develop and function properly, but there’s still a lot scientists don’t understand about how astrocytes perform these important jobs. Now, a team of scientists led by Associate Professor Nicola Allen has found one way that neurons and astrocytes work together to form healthy connections called synapses. This insight into normal astrocyte function could help scientists better understand disorders linked to problems with neuronal development, including autism spectrum disorders. The study was published in the journal eLife.

“We know that astrocytes could play a role in neurodevelopmental disorders, so we wanted to ask: How are they playing a role in typical development?” says Allen, a member of the Molecular Neurobiology Laboratory. “In order to better understand the disorders, we first have to understand what happens normally.”

Synapses form critical connections between neurons, allowing neurons to send signals and information throughout the body. Astrocyte cells play a role in synapse development by giving neurons directions, such as telling them when to start growing a synapse, when to stop, when to prune it back, and when to stabilize the connection.

Allen and her team took a closer look at how this process plays out in the visual cortex of the mouse brain. They sequenced the RNA of astrocytes at different stages of brain development to assess gene activity and compared it with neuronal synapse development. They found that astrocyte signaling was directly related to each stage of neuronal development. The researchers then wanted to know how the astrocytes knew to make these signals at the right time.

First, the researchers looked at what happened to the astrocytes when they changed the neurons’ activity. To do this, they stopped neurons from releasing a neurotransmitter called glutamate that can signal to astrocytes, and this stopped the astrocytes from showing the typical developmental changes. Next, the scientists stopped the astrocytes from responding to neurotransmitters, and found this stopped the astrocytes from expressing the right signals. With both these manipulations, the development of synapses was also disrupted, in line with the changes observed in the astrocytes.

Collectively, the findings suggest that astrocytes are responding to neurotransmitters produced by neurons to control the timing of when astrocytes produce signals to instruct neuronal development, according to Allen.

“It makes sense that you have this constant feedback going on between the neuron and the astrocyte,” says Allen. “They are sending signals to each other: ‘Am I in the right place?’ ‘Yes, you are.’ ‘I’ve made a connection now—do I keep it?’ ‘Yes, you do.’ And they keep going back and forth.”

Next, Allen and her team are studying whether these signals can be manipulated—for example, to stimulate neurons to repair synapses or form new ones in disorders of aging, such as Alzheimer’s disease.

(Image caption: Astrocytes (green) and neurons (magenta) closely interact in the developing cortex and signal to each other to ensure correct development. Credit: Salk Institute)

Cholesterol Drives Alzheimer’s Plaque Formation

Cholesterol manufactured in the brain appears to play a key role in the development of Alzheimer’s disease, new researchindicates.

Scientists from the School of Medicine and their collaborators found that cholesterol produced by cells called astrocytes is required for controlling the production of amyloid beta, a sticky protein that builds up in the brains of patients with Alzheimer’s. The protein accumulates into insoluble plaques that are a hallmark of the disease. Many efforts have targeted these plaques in the hope that removing or preventing them could treat or prevent Alzheimer’s.

The new findings offer important insights into how and why the plaques form and may explain why genes associated with cholesterol have been linked to increased risk for Alzheimer’s. The results also provide scientists with important direction as they seek to prevent Alzheimer’s from developing.

“This study helps us to understand why genes linked to cholesterol are so important to the development of Alzheimer’s disease,” said researcher Heather A. Ferris, MD, PhD, of UVA’s Division of Endocrinology and Metabolism. “Our data point to the importance of focusing on the production of cholesterol in astrocytes and the transport to neurons as a way to reduce amyloid beta and prevent plaques from ever being formed.”

Alzheimer’s Plaques and Cholesterol

While cholesterol is often associated with clogged arteries and heart disease, it plays important roles in the healthy body. The body makes cholesterol naturally so it can produce hormones and carry out other important functions. The new discovery from Ferris and her collaborators adds a new entry to cholesterol’s list of responsibilities.

The work also sheds light on the role of astrocytes in Alzheimer’s disease. Scientists have known that these common brain cells undergo dramatic changes in Alzheimer’s, but they have been uncertain if the cells were suffering from the disease or contributing to it. The new results from Ferris and her collaborators suggest the latter.

The scientists found that astrocytes help drive the progression of Alzheimer’s by making and distributing cholesterol to brain cells called neurons. This cholesterol buildup increases amyloid beta production and, in turn, fuels plaque accumulation.

Normally, cholesterol is kept quite low in neurons, limiting the buildup of amyloid beta. But in Alzheimer’s, the neurons lose their ability to regulate amyloid beta, and the result is plaque formation.

Blocking the astrocytes’ cholesterol manufacturing “robustly” decreased amyloid beta production in lab mice, the researchers report in a new scientific paper. It’s too soon to say if this could be mimicked in people to prevent plaque formation, but the researchers believe that further research is likely to yield important insights that will benefit the battle against Alzheimer’s.

The fact that amyloid beta production is normally tightly controlled suggests that it may play an important role in brain cells, the researchers say. As such, doctors may need to be careful in trying to block or remove amyloid beta. Additional research into the discovery could shed light on how to prevent the over-production of amyloid beta as a strategy against Alzheimer’s, the researchers believe.

“If we can find strategies to prevent astrocytes from over-producing cholesterol, we might make a real impact on the development of Alzheimer’s disease,” Ferris said. “Once people start having memory problems from Alzheimer’s disease, countless neurons have already died. We hope that targeting cholesterol can prevent that death from ever occurring in the first place.”