Under the Microscope: Nerve Glue and the Evolution of Psychiatric Neuroscience

In December 1993, at the annual meeting of the American College of Neuropsychopharmacology, psychiatrist David Healy was bored. So, he decided to try something. He approached several well-known psychiatrists and scientists and asked if they’d be willing to talk about their life and work. The stories were amazing: from the discovery of the monoamine system, to the first human trials of reuptake inhibitors, to how antipsychotics evolved from the mysterious chlorpromazine to highly specific D₂ antagonists. He ultimately compiled these interviews into a 4-volume series entitled The Psychopharmacologists (1). In many ways, these stories inform the identity of the modern psychiatrist.

But they also contain an unsettling truth. Arvid Carlson, a Nobel Laureate for his work on dopamine, questioned the dopamine hypothesis of schizophrenia. Joseph Schildkraut, who popularized the monoamine hypothesis of depression, admitted that he cringed when depression was labeled as a mere biochemical deficiency. While The Psychopharmacologists highlights the extraordinary progress of the past 70 years, it is also a confessional that our understanding of brain function and dysfunction is far from complete.

One emerging story goes back more than a century. In 1873, 17-year-old Sigmund Freud had just entered medical school. Drawn to innovations in microscopy, Freud pioneered novel staining techniques to characterize the nervous system (2). He was intent on continuing this research but, due to pervasive antisemitism, was unable to obtain a faculty position at the University of Vienna. Instead, he studied hypnosis and hysteria under the neurologist Jean-Martin Charcot, and his career took a distinct turn (3). Fortunately, his cellular work was picked up by two other neuroanatomists, Camillo Golgi and Santiago Ramón y Cajal.

By developing new staining methods, Golgi and Ramón y Cajal were able to visualize the brain with unprecedented resolution. And yet, they came to different conclusions. Golgi suggested that what appeared to be distinct cells in the brain were all interconnected through a series of fibers, thus forming a single reticulum; in contrast, Ramón y Cajal proposed that each cell represented a discrete entity—a model he called the Neuron Doctrine (4). According to Ramón y Cajal, axons of neurons transmit signals to other neurons across a physical gap—what eventually would become known as a synapse.

As a testament to both Golgi’s and Ramón y Cajal’s pioneering work, they shared the Nobel Prize in 1906. Ramón y Cajal’s Neuron Doctrine ultimately prevailed: the neuron came to be thought of as the fundamental unit of brain function, and the synapse as the fundamental unit of brain communication. But there was a problem with the model: it largely ignored more than half the cells in the brain. It was assumed that these cells, collectively known as neuroglia (literally nerve glue, from the Greek glia), primarily had a structural role, providing a supportive scaffolding for neurons. But others suspected that they did more.

The first attempt at incorporating glia into a model of brain signaling was made by Carl Ludwig Schleich (5). From an early age, Schleich was interested in religion and intended to become a priest. But he was also interested in science. Even when he eventually decided to study medicine, he remained fascinated by basic existential questions: what is it that makes us who we are? And how is it that a group of cells can come together to create the complexity of human experience?

Contemporary models of brain function were based entirely on neuronal excitation—but Schleich realized that there were certain processes that could not be explained this way. For example, how is it that individuals can take in a broad field of vision and selectively focus onto one element? There had to be a way for the brain to inhibit signals. Schleich proposed that glial cells swell and shrink based on their “humour.” In a swollen state, the cell can insulate the neuron and insert itself in the gap between two neurons, thus blocking electrical signaling.

Schleich’s idea was dismissed by some of his peers, who called it a mere “curiosity” and a “figment of the imagination.” The subsequent discovery of chemical transmission between neurons [based on Otto Loewi’s 1921 description of the inhibitory effect of Vagussstoff on the heart (6)] obviated the need for any additional cells to explain the working of the synapse.

For most of the 20th century, research focused on the role of neurons. Then a suite of new tools—from ion-sensitive fluorescent indicators to confocal microscopy—allowed scientists to expand their field of vision.

Phil Haydon is a leading researcher who used these tools to describe the extraordinary properties of a star-shaped glial cell, the astrocyte. Each astrocyte can contact up to 100,000 synapses (7). Moreover, they have the ability to detect activity at one synapse and pass the signal to other synapses via non-action potential, calcium signaling. He also demonstrated that astrocytes release glutamate onto nearby presynaptic terminals to modulate neurotransmitter release. Depending on action at presynaptic mGlu receptors or extrasynaptic NMDA receptors, astroglia can either depress or enhance activity at the synapse. Haydon’s findings challenged more than a century of neuroscience dogma. He redefined the functional unit of communication in the brain from a dyadic process to a tripartite synapse consisting of 1) the terminal of an axon, 2) the postsynaptic neuron, and 3) the astrocyte (8).

Two thousand miles away from Haydon’s lab in Iowa, Ben Barres was at Stanford exploring a longstanding research issue: neurons simply didn’t grow in culture the way that they grow in brains. Barres wanted to know why. Along with his colleagues, he developed a technique called immunopanning through which they could selectively tag and then isolate a specific cell type. Using this tool, he created a culture of pure astrocytes, extracted the medium, and then added that liquid to a separate culture of pure neurons (in this case, retinal ganglion cells). As he suspected, the neurons grown in the astrocyte-conditioned medium had a larger number of synapses and transmitted information more efficiently (9). He went on to show that the magic ingredient was a glycoprotein called thrombospondin 1 (TSP1) (10).

TSP1 turned out to be just the tip of the iceberg. In the years since, researchers have identified a wide range of astrocyte-mediated growth factors, neurotransmitters, and cytokines. One key process through which these chemicals exert their influence is known as reactive astrogliosis: when the brain is injured (as from trauma), astrocytes proliferate and release these factors to protect surviving neurons and eliminate injured ones.

They also seem to play a critical role in psychiatric illness. For example, when astrocyte function is compromised (e.g., by impaired calcium signaling or reduced glucocorticoid input), rodents develop depressive-like behavior (11). Similarly, postmortem studies in humans with depression have found lowered astrocyte densities and lowered glutamate transporter levels in these cells (12). A recent review summarized evidence supporting astroglial dysfunction in depression (13).

Of course, there are limitations to both animal models and postmortem studies. What is missing is the ability to probe the function of human astrocytes. While there is no easy way to access living brain tissue, recent innovations offer a clever approach. It’s now possible to take a skin or blood cell, reprogram it into an embryonic-like state (an induced pluripotent stem cell [IPSC]), and then differentiate it into any cell type of interest. In one example, a team of researchers at the Salk Institute recruited individuals with and without depression and compared the function of IPSC-derived astrocytes. They found that the astrocytes from individuals with depression responded differently to cortisol, perhaps connecting to known abnormalities in the hypothalamic-pituitary-adrenal axis (14).

Similar research is emerging for schizophrenia, bipolar disorder, and autism. Not only do astrocytes from individuals with psychiatric disorders have different characteristics than those of healthy control participants, but there are also differences based on their clinical profiles. For example, one study enrolled individuals with schizophrenia who had either responded to or failed a trial with clozapine. Astrocytes from both groups had deficits in glutamate. The cool part is what happened next: When they exposed astrocytes to clozapine, glutamate levels normalized—but only in the group of clinical responders (15). While this type of work is still in the earliest phases, the hope is that it will ultimately lead to the development of biomarkers, new treatments, and other precision medicine approaches.

In hindsight, we can see that The Psychopharmacologists— the cutting edge of late 20th century psychiatry—was missing a huge part of the story. One can still find research on serotonin and norepinephrine in Biological Psychiatry, but it is surrounded by other articles on the role of astroglia, glutamate, and the gut-brain axis. Clinical trials of drugs sit next to studies on neuromodulation—whether via common interventional tools, like repetitive transcranial magnetic stimulation or transcranial direct current stimulation, or via psychosocial interventions, like exercise, which also modulate neural circuits. When today’s researchers are interviewed for the next iteration of this series, the field will be ready for a new identity and the book will be ready for a new name: The Clinical Neuroscientists.