We have within us the most complex and inspiring stage to ever be set: the human brain. The cellular components of the brain act as players, interacting through chemical and electrical signaling to elicit emotions and convey information. Although most of our attention has in the past been focused on neurons, which were erroneously presumed to act alone in their leading role, scientists are slowly realizing that astrocytes—glial cells in the brain that were previously assumed to only have a supportive role in association with neurons—are so much more than merely supporting characters.
Though neurons are the stars, most of the brain is actually composed of supportive cells like microglia, oligodendrocytes, and, most notably, astrocytes. Astrocytes, whose formal name is a misnomer given that modern imaging technology reveals they actually maintain a branch-like shape rather than a star-like one, exist as one of three mature types in the grey matter, white matter, or retina. Structurally, the grey matter astrocyte variant exhibits bushy, root-like tendrils and a spherical shape. The white matter variant, commonly found in the hippocampus, favors finer extensions called processes. The retinal variant features an elongated structure.¹
Functionally, astrocytes were previously believed to play a solely supportive role, as they constitute a large percentage of the glial cells present in the brain. Glial cells are essentially all of the non-neural cells in the brain that assist in basic functioning; they themselves are not electrically excitable. However, current research suggests that astrocytes play far more than merely a supporting role in the brain. Astrocytes and neurons directly interact to interpret stimuli and store memories⁴, among many other yet undiscovered tasks.
Although astrocytes are not electrically excitable, astrocytes communicate with neurons via calcium signaling and the neurotransmitter glutamate.² Calcium signaling works whereby intracellular calcium in astrocytes is released upon excitation and is propagated in waves that move through neighboring astrocytes and neurons. Neurons experience a responsive increase in intracellular calcium if they are directly touching affected astrocytes, as the signal is communicated via gap junctions rather than synaptically. Such signalling is unidirectional; calcium excitation can move from astrocyte to neuron, but not from neuron to astrocyte.³ The orientation of astrocytes in different regions of the brain and their proximity to neurons allows them to form close communication networks that help information travel throughout the central nervous system.
Astrocytes in the hippocampus play a role in memory development. They act as an intermediary cell in a neural inhibitory circuit that utilizes acetylcholine, glutamate, and Gamma-Aminobutyric Acid (GABA) to solidify experiential learning and memory formation. Disruption of cholinergic signaling, signaling relating to acetylcholine, prohibits the formation of memories in the dentate gyrus of the hippocampal formation. Astrocytes act as mediators that convert cholinergic inputs into glutamatergic activation of neurons.⁴ Without the assistance of astrocytic networks in close association with neurons, memory formation and long-term potentiation would be far less efficient if even still possible.
Astrocytes’ ability to interpret and release chemical neurotransmitters, especially glutamate, allows them to regulate the intensity of synaptic firing in neurons.⁵ Increased glutamate uptake by astrocytes reduces synaptic strength in associated neurons by decreasing neuronal concentration of glutamate.⁶ Regulation of synaptic strength in firing is crucial for healthy brain function. If synapses fire too much or too powerfully, they may overwhelm the brain. Conversely, if synapses fire too infrequently or not strongly enough, messages might not make their way throughout the central nervous system. The ability of astrocytes to modulate synaptic activity through selective glutamate interactions puts them in an integral position to assist in consistent and efficient transmission of information throughout the human body.
Through regulation of neurotransmitters and psychoactive chemicals in the brain, astrocytes are able to maintain homeostasis in the central nervous system. Potassium buffering and balancing of pH are the major ways that astrocytes assist in maintaining optimal conditions for brain function.⁷ Astrocytes are able to compensate for the slow re-uptake of potassium by neurons, thus decluttering the extracellular space of free potassium in response to neuronal activity. Re-uptake of these ions is extremely important to brain function as synaptic transmission by neurons relies on electrically switching membrane potentials along neuronal axons.
Due to their role in synaptic regulation and their critical position in the brain network, astrocytes also have the potential to aid in therapies for dealing with neurological disorders. For example, epileptic seizures have been found to be related to an excitatory loop between neurons and astrocytes. Focal ictal discharges, the brain activity responsible for epileptic seizures, are correlated to hyperactivity in neurons as well as an increase in intracellular calcium in nearby astrocytes; the calcium oscillations then spread to neighboring astrocyte networks to perpetuate the ictal discharge and continue the seizure. Astrocytes in epileptic brain tissues exhibit structural changes that may favor such a positive feedback loop. Inhibition of calcium uptake in astrocytes, and consequent decrease in release of glutamate and ATP, is linked to suppression of ictal discharges, and therefore linked to a decrease in the severity and occurrence of epileptic seizures.⁸ Furthermore, it is evident that astrocyte activity also plays a role in memory loss associated with Alzheimer’s Disease. Although astrocytes in the hippocampus contain low levels of the neurotransmitter GABA under normal conditions, hyperactive astrocytes near amyloid plaques in affected individuals exhibit increased levels of GABA that are not evident in other types of glial cells. GABA is the main inhibitory neurotransmitter in the brain, and abnormal increases in GABA are associated with Alzheimer’s Disease; introducing antagonist molecules has been shown to reduce memory impairment, but at the cost of inducing seizures.⁹ Since there is a shift in GABA release by astrocytes between normal and diseased individuals, astrocytes could be as the key to remedying neurodegenerative conditions like Alzheimer’s.
In addition to aiding in treatment of neurological disorders, astrocytes may also help stroke victims. Astrocytes ultimately support damaged neurons by donating their mitochondria to the neurons.¹⁰ Mitochondria produce adenosine triphosphate (ATP) and act as the energy powerhouse in eukaryotic cells; active cells like neurons cannot survive without them. Usually neurons accommodate their exceptionally large energy needs by multiplying their intracellular mitochondria via fission. However, when neurons undergo stress or damage, as in the case of stroke, the neuron is left without its source of energy. New research suggests that astrocytes come to the rescue by releasing their own mitochondria into the extracellular environment in response to high levels of the enzyme CD38, so that damaged neurons can absorb the free mitochondria and survive the damage.¹¹ Astrocytes also help restore neuronal mitochondria and ATP production post-insult by utilizing lactate shuttles, in which astrocytes generate lactate through anaerobic respiration and then pass the lactate to neurons where it can be used as a substrate for oxidative metabolism¹². Such a partnership between astrocytes and neurons presents researchers with the option of using astrocyte-targeted therapies to salvage neuronal systems in stroke victims and others afflicted by ailments associated with mitochondrial deficiencies in the brain.
Essentially, astrocytes are far more than the background supporters they were once thought to be. Before modern technological developments, the capabilities and potential of astrocytes were left woefully unnoticed. Astrocytes interact both directly and indirectly with neurons through chemical signaling to create memories, interpret stimuli, regulate signaling, and, maintain a healthy central nervous system. A greater understanding of the critical role astrocytes play in the human brain could allow scientists to develop astrocyte-targeted therapeutic practices. As astrocytes slowly inch their way into the spotlight of neuroscientific research, there is so much yet to be discovered.
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