By Danielle Gerhard
Recent estimates by the National Institute for Mental Health (NIMH) have found that approximately 25% of American adults will experience a mental illness within a given year. Individuals living with a serious mental illness are more likely to develop a chronic medical condition and die earlier. In young adults, mental illness results in higher high school drop out rate. A dearth of effective medications leaves many individuals unable to hold a job, causing America a $193 billion loss in earnings per year. These saddening statistics shed light on the need for better drugs to treat mental illness.
Traditionally, treating a mental illness like depression, anxiety or schizophrenia involves a delicate and perpetually changing combination of drugs that target levels of neurotransmitters in the brain. Neurotransmitters are chemicals produced by the brain and used by cells to communicate with one another. Drugs used to treat mental illness either increase or decrease the release, reuptake or degradation of these chemicals from the cell. The current paradigm is that the disease solely results from neurotrasmitter imbalance. Therefore, research has predominantly focused on the specific types of cells that release them. However, neurons make up approximately 50% of all cells in the human brain. The other 50% of brain cells are glial cells and are responsible for maintaining and protecting the neurons in the brain and body.
One type of glial cell, microglia, are specialized macrophage-like immune cells that migrate into the brain during development and reside there throughout life. Microglia are the primary immune cells in the brain and act as first-responders, quickly mounting responses to foreign pathogens and promoting adaptive immune actions. Microglia can adapt to changes in their microenvironment by protracting or retracting their processes to maintain neuronal health, scavenging their surroundings for dead neurons and cellular debris. Moreover, it has been shown that microglia are involved in the induction and maintenance of long-term potentiation, an event that is critical for synaptic plasticity underlying learning and memory. Only in the past decade or so has this cell type begun to surface as a potential mediator in the development and continuation of mental illness. As a result of decades of neuron-focused experiments, the function of microglia have either been misunderstood or over-looked all together. Two recently published experiments contradict our conventional understanding of the etiology of mental illness.
A new study published in the January 29th issue of the scientific journal Nature Communciations by Dr. Jaime Grutzendler’s team at Yale University highlights a novel role for microglia in Alzheimer’s Disease (AD). Late-onset AD is thought to result from the accumulation of the protein β-amyloid (Αβ). This process is referred to as plaque aggregation and results from reduced Aβ plaque clearance. Because microglia with an activated morphology are found wrapped around areas of high Aβ accumulation, it has been hypothesized that they actually contribute to weakened neuronal projections by releasing small neurotoxic proteins, cytokines, that affect cell communication. Aβ can exist as mature and inert fibrillar Aβ but can also revert back to an intermediatary state, protofibrillar Aβ, which is toxic to neurons.
Dr. Grutzendler’s lab set out to to further investigate the role of microglia in Aβ plaque expansion with respect to the different forms of Aβ. Using two-photon imaging and high-resolution confocal microscopy, the team at Yale was able to show that, for the most part, microglia formed tight barriers around Aβ plaques with their processes, but in some instances microglia left plaque “hotspots” exposed. These plaque “hotspots” were associated with greater axonal and neuronal damage.
These findings indicate that microglia generated protective barriers around Aβ plaques that served to protect neurons from the neurotoxic effects of protofibrillar Aβ. Of note, studies using aged mice revealed that microglia were less effective at surrounding plaques leading to increased neuronal damage. Microglia regulation decreases with age thereby rendering neurons more vulnerable to environmental insults. This cell type is therefore a likely key mediator of neuronal death that leads to cognitive decline and emotional distrubances in patients suffering from AD and other neurogegenerative diseases.
Another recently published study highlights a novel role of microglia in addiction, a chronic disease that afflicts many individuals with mental illness, comes from Dr. Linda Watkins, of the University of Colorado, Boulder. The study, published in the February 3rd issue of the scientific journal Molecular Psychiatry, examines the role of microglia in the rewarding and reinforcing effects of cocaine.
It has long been understood that drugs of abuse cause activation of the dopamine (DA) system in the brain, with increased DA release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), a brain region important for their rewarding effects. Cocaine achieves this effect by blocking dopamine transporters (DATs) on the cell, resulting in increased levels of synaptic DA and sustained neuronal activity. Therefore, efforts have focused on targeting DATs to prevent the rewarding effects of cocaine and ultimately reduce addiction.
In addition to these established dogmas, recent studies have shown that cocaine also activates the brain’s immune system. Microglia express Toll-like receptor 4 (TLR4) and its binding protein MD-2, which are important for reconizing pathogens and activating the release of pro-inflammatory molecules such as interleukin-1β (IL-1β). Using an animal model of addiction in combination with in silico and in vitro techniques, Dr. Watkin’s team found that cocaine activates the TLR4/MD-2 complex on microglia, resulting in an upregulation of IL-1β mRNA in the VTA and increased release of DA in the NAc. Administration of the selective TLR4 antagonist (+)-naloxone blocked the cocaine-induced DA release and the rewarding effects of cocaine administration in the rodent self-administration behavioral models. Overall, the study concludes that TLR4 activation on microglial cells contributes to the rewarding and reinforcing properties of cocaine. Thus, drugs targeting this system could provesuccessful in treating addiction.
Through these studies and similar reports, it is becoming apparent that mental illness is more than a chemical imbalance in the brain and therefore shouldn’t be studied as such. The two studies highlighted in this article show the diverse role of microglia in the development and maintenance of mental illnesses. A more in-depth understanding of how this cell type interacts with already identified neural systems underlying mental disorders could result in the development of better-tailored drug design.