Neuroscience doctoral student receives NIH award to study the little-known astrocyte
Behind our thoughts, our behaviors, and our movements are firing neurons. These foundational brain cells communicate with one another to mediate the many things our brains do via contact points known as synapses. But behind that activity is a brain cell that’s received far less study throughout the history of neuroscience: the astrocyte.
These cells have complex, sponge-like shapes with thousands of branches from their cell body that allow them to interact with thousands of things at once. They’re involved in nearly every aspect of what keeps the brain going, Ceja Pinkston said, including brain development, maintaining homeostasis, formation of the blood-brain barrier, and all things neurons.
“If we imagine our brain as a garden, neurons are like the beautiful flowers that keep us going,” Ceja Pinkston said. “But the astrocytes are like the soil that is maintaining those flowers, feeding those flowers, and providing all the nutrients and all the richness and goodness to make those flowers bloom.”
Supported by the Ruth L. Kirschstein Predoctoral Individual National Research Service Award from the National Institutes of Health, Ceja Pinkston will explore a fundamental question about astrocytes: What first draws them to synapses to support all of this action? She believes that understanding astrocytes in this way could help scientists fill knowledge gaps in how neurodevelopmental disorders arise and how to treat them.
The Olsen Lab is run by Michelle Olsen, an associate professor of neuroscience in the Virginia Tech College of Science.
“I'm just fascinated by the fact that even a singular astrocyte can be involved in so many different aspects of the brain,” Ceja Pinkston said. “It’s the fact that we don’t understand everything about it that just makes me itch. I need to answer all these questions.”
Much of the role astrocytes play in supporting brain function happens at synapses, which are the contact points of communication between neurons. Astrocytes come and “cradle” synapses by way of perisynaptic astrocytic processes, also known as leaflets, millions of which extend from the astrocyte’s many branches. When these leaflets come in to cradle a synapse, Ceja Pinkston said, they enable astrocytes to maintain ion and neurotransmitter — chemicals in the brain that help neurons communicate — homeostasis at the synapse; provide synapses with structural support; and release molecules that increase synapse development and maturation.
Ceja Pinkston wants to know what draws astrocytes to those contact points. She believes that astrocyte leaflets could be originally drawn to synapses by Brain-Derived Neurotrophic Factor (BDNF). For decades, BDNF has been recognized as important for the development, maturation, and survival of neurons, which release the molecule to attract other neurons to their synaptic terminals and in the process encourage the formation of new synapses. Neurons have receptors for the molecule known as TrkB.
Recently, however, the Olsen Lab discovered that astrocytes have their own kind of receptor for BDNF, called TrkB.T1. This receptor, a truncated version of TrkB, is predominantly expressed by astrocytes, which means that astrocytes may actually be the predominant cell to receive BDNF, Ceja Pinkston said.
During that previous study, the researchers found that BDNF is critical to the development of astrocytes: When BDNF binds to the TrkB.T1 receptor early in astrocyte development, it allows astrocytes to develop their complex, spongiform morphology. The absence of this receptor also results in immature astrocytes, which the researchers believe could affect their ability to cradle synapses and support synapse formation.
To take a closer look at BDNF activity at synapses, Ceja Pinkston plans to use electron microscopy to zoom into the synapse as she stimulates specific regions of the brain in mice with a tickle to their individual whiskers. Each of a mouse’s whiskers has a corresponding area of the brain, known as a “whisker barrel,” that encodes all the information that is obtained by that whisker as the mouse navigates its environment.
As she stimulates whiskers, triggering the development of new synapses, Ceja Pinkston will examine how this stimulation and the resulting increase in synapses — which in turn releases BDNF — may attract astrocyte leaflets to developing synapses. With this method, she can make fine-grained observations of astrocyte leaflets, which are often difficult to image using conventional microscopy due to their nanoscale sizes.
Learning what draws astrocytes to synapses could give a more complete picture of the interconnected functions of astrocytes, synapses, and neurons and how problems among these players result in autism spectrum disorders, ADHD, and other neurodevelopmental disorders as well as neuropsychiatric disorders involving both synapses and BDNF.
“The reason why we may not have the full story yet is because we’ve only been looking at these neurodevelopmental and neuropsychiatric disorders from the perspective of neurons,” Ceja Pinkston said. “If we were to look at it from the perspective of astrocytes, it could open up or answer so many questions that the field currently has. Now that we have this third unacknowledged partner, how can we bring it into play in our studies to have a better understanding of our disease models? Answering this question is also just fundamental to our general knowledge of the central nervous system.”
From there, Ceja Pinkston foresees a path to providing novel therapeutic agents for disorders tied to a lack of synapse formation or to immature synapses. “If we could say, now we know that BDNF attracts astrocytes to these synapses, could we perhaps find a very specific drug molecule that would be specific to astrocytes and attract them to these problematic synapses?” Ceja Pinkston said.
For Ceja Pinkston, it all hinges on scratching the itch that first brought her to the Olsen Lab: the need to answer the basic questions that still surround the little-known astrocyte.