In 1993, David Healy compiled stories of major discoveries in modern psychiatry, such as advances in antidepressants and antipsychotics, in his book The Psychopharmacologists. These interviews showcased scientific achievements and the limits of our understanding of the brain. Despite the traditional focus on neurons, recent studies have revealed the importance of glial cells, especially astrocytes, in brain communication and health.
In December 1993, at the American College of Neuropsychopharmacology annual meeting, psychiatrist David Healy was bored. So he decided to try something new. He approached several prominent psychiatrists and scientists and asked if they would be willing to talk about their lives and work.
The stories were incredible: from the discovery of the monoamine system, the first human trials of reuptake inhibitors, and how antipsychotics evolved from the mysterious chlorpromazine to highly specific D2 antagonists.
He eventually compiled these interviews into a four-volume series titled The Psychopharmacologists. In many ways, these stories inform the identity of the modern psychiatrist.
But they also contain an unsettling truth. Arvid Carlson, a Nobel Prize winner 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 a mere biochemical deficiency.
While The Psychopharmacologists highlight the extraordinary progress of the past 70 years, it is also a confession that our understanding of brain function and dysfunction is far from complete.
An emerging story goes back more than a century. In 1873, 17-year-old Sigmund Freud had just entered medical school. Attracted by innovations in microscopy, Freud pioneered new staining techniques to characterize the nervous system.
He intended to continue this research, but because of widespread anti-Semitism, he was unable to obtain a teaching position at the University of Vienna. Instead, he studied hypnosis and hysteria with the neurologist Jean-Martin Charcot, and his career took a different turn.
Fortunately, his cellular work was picked up by two other neuroanatomists, Camillo Golgi and Santiago Ramón y Cajal.
Sigmund Freud
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 by 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.
According to Ramón y Cajal, the axons of neurons transmit signals to other neurons across a physical gap—what would eventually become known as a synapse.
As a testament to Golgi and Ramón y Cajal’s pioneering work, they shared the Nobel Prize in 1906. Ramón y Cajal’s Neuron Doctrine eventually prevailed: the neuron came to be regarded as the fundamental unit of brain function, and the synapse as the fundamental unit of brain communication.
Drawing (A) and images (B, C) from Golgi-impregnated pes Hippocampi major (Ammon's horn) of the rabbit. (A) The drawing is Plate XIII from Golgi (1885), the translation of the original figure legend is provided by Bentivoglio and Swanson in Golgi et al. (2001). In the figure legend, Golgi noted the “different shapes presented by these cells.” The initial part of the “nerve process” (the axon) is drawn in red, and Golgi noted in the legend that “it should be considered a general rule that this part ramifies into numerous secondary fibrils that branch profusely.” (B, C) Impregnated neurons in Golgi's slides, showing what he should have seen. Scale bars: 200 μm in (B), 50 μm in (C). Image: Front. Neuroanat., Bentivoglio et al., Volume 13 - 2019 |
But the model had a problem: It largely ignored more than half of the brain's cells. These cells, known collectively as neuroglia (literally nerve glue, from the Greek glia), were thought to have a primarily structural role, providing scaffolding for neurons. But others suspected that they did more.
The first attempt to incorporate glia into a model of brain signaling was made by Carl Ludwig Schleich. Schleich had been interested in religion from an early age and intended to become a priest, but he was also interested in science.
Even when he finally decided to study medicine, he remained fascinated by basic existential questions: What makes us who we are? And how can a group of cells come together to create the complexity of the 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 that way.
For example, how is it that individuals can have a wide field of vision and focus selectively on 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 "mood." In a swollen state, the cell can isolate the neuron and insert itself into the space between two neurons, thus blocking electrical signaling.
Schleich’s idea was dismissed by some of his colleagues as a mere “curiosity” and a “fiction of the imagination.” The subsequent discovery of chemical transmission between neurons (based on Otto Loewi’s 1921 description of the inhibitory effect of Vagusstoff in the heart) eliminated the need for any additional cells to explain how the synapse works.
For most of the 20th century, research focused on the role of neurons. Then a suite of new tools, from ion-sensitive fluorescent markers to confocal microscopy, allowed scientists to expand their field of vision.
Phil Haydon is a leading researcher who has 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. Furthermore, 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 at nearby presynaptic terminals to modulate neurotransmitter release.
Depending on the action on presynaptic mGlu receptors or extrasynaptic NMDA receptors, astroglia can either depress or enhance activity at the synapse.
Haydon's discoveries challenged over 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) an axon terminal, 2) a postsynaptic neuron, and 3) an astrocyte.
Two thousand miles away from Haydon’s lab in Iowa, Ben Barres was at Stanford exploring a long-standing research problem: neurons simply didn’t grow in culture the way they do in brains.
Barres wanted to know why. Together with his colleagues, he developed a technique called immunopanning, through which they could selectively label and isolate a specific type of cell.
Immunopanning schematic overview of the protocol for human glial-cell enrichment. Image: Nolle et al. Front. Cell. Neurosci., Volume 15 - 2021 |
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 greater number of synapses and transmitted information more efficiently. He went on to show that the magic ingredient was a glycoprotein called thrombospondin 1 (TSP1).
TSP1 turned out to be just the tip of the iceberg. In the years that followed, researchers identified a wide range of astrocyte-mediated growth factors, neurotransmitters, and cytokines.
A key process by which these chemicals exert their influence is known as reactive astrogliosis: when the brain is injured (such as by trauma), astrocytes proliferate and release these factors to protect surviving neurons and eliminate injured ones.
They also appear to play a critical role in psychiatric illnesses. For example, when astrocyte function is compromised (e.g., by impaired calcium signaling or reduced glucocorticoid uptake), rodents develop depressive-like behavior.
Similarly, postmortem studies in humans with depression have found reduced astrocyte densities and reduced levels of glutamate transporters in these cells. A recent review summarized the evidence supporting astroglial dysfunction in depression. Of course, there are limitations to both animal models and postmortem studies.
What is lacking is the ability to probe human astrocyte function. While there is no easy way to access living brain tissue, recent innovations offer a clever approach. It is now possible to take a cell from the skin or blood, reprogram it to an embryonic state (an induced pluripotent stem cell [IPSC]), and then differentiate it into any cell type of interest.
Culture of human iPSC-derived dopaminergic neurons. (A–D) Differentiation of human iPSC-derived neural progenitor cells into dopaminergic neurons from day 0 to 14 after seeding the cells in 96-well plates at 3 × 104 cells per well. (A) day 0 (B) day 1, (C) day 7, (D) day 14. (E) Human dopaminergic neurons (14 days after seeding) were stained with anti-beta III-tubulin (green), a neuronal cell marker. (F) Anti-tyrosine hydroxylase (red), a dopaminergic neuronal marker. Cells were counterstained with DAPI (blue). Scale bar = 50 μm. Source: Ketamine Causes Mitochondrial Dysfunction in Human-Induced Pluripotent Stem Cell-Derived Neurons. DOI: 10.1371/journal.pone.0128445
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 astrocytes from individuals with depression responded differently to cortisol, perhaps linked to known abnormalities in the hypothalamic-pituitary-adrenal axis.
Similar research is emerging for schizophrenia, bipolar disorder, and autism. Not only do astrocytes from individuals with psychiatric disorders have different characteristics than those from healthy control participants, but there are also differences based on their clinical profiles.
For example, one study enrolled individuals with schizophrenia who either responded or failed a clozapine trial. 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 clinical responder group.
While this kind of work is still in its early stages, the hope is that it will eventually lead to the development of biomarkers, new treatments, and other precision medicine approaches.
In retrospect, we can see that The Psychopharmacologists, the vanguard of late-20th-century psychiatry, were missing a big part of the story. You can still find research on serotonin and norepinephrine in Biological Psychiatry, but it’s surrounded by other papers on the role of astroglia, glutamate, and the gut-brain axis.
Clinical drug trials sit alongside studies on neuromodulation, whether through common interventional tools like repetitive transcranial magnetic stimulation or transcranial direct current stimulation, or through psychosocial interventions like exercise, which also modulate neural circuits.
By the time 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.
READ MORE:
Under the Microscope: Nerve Glue and the Evolution of Psychiatric Neuroscience
Sukumar Vijayaraghavana, David A. Rossb, and Andrew M. Novickc
Biological Psychiatry, Volume 96, Issue 9E11-E13, November 01, 2024
DOI: 10.1016/j.biopsych.2024.08.017
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