From Teach

Isolated astrocyte

The role of astrocytes in learning and memory has been a recent area of research and study. Originally viewed as passive participants in synaptic function, new studies indicate that these star-shaped glial cells play a much larger role in regulating essential brain functions such as information processing, plasticity, learning and memory.

By comparing human astrocytes to the astrocytes in nonhuman primates and mice, it has been found that human cortical astrocytes are larger, more complex, and more diverse. The astrocyte complexity in humans contributes to the enhanced functional competence in the human brain.





Description

The astrocyte is a ubiquitous type of glial cell and the most abundant cell in the human brain, greatly outnumbering neurons and occupying 20%-50% of brain volume. Astrocytes are found surrounding neurons and synapses and are recognized by their star-shaped appearance. They are divided into different types, including protoplasmic astrocytes, interlaminar astrocytes, polarized astrocytes, and fibrous astrocytes. Astrocytes have several essential functions in the Central Nervous System, such as blood flow regulation, energy metabolism, ion and water homeostasis, immune defense, neurotransmission, and adult neurogenesis.

For many years, astrocytes were thought to only provide support to electrically active neurons involved in information processing in the brain. Because astrocytes cannot generate electrical signals, it was assumed that they did not have an active role in neural signaling. However, in the past few decades, an increase in interest and research of these cells has emerged. Researchers have discovered the incredible morphologic and functional diversity of astrocytes, uncovered several functions of astrocytes in neural signaling, and have a better understanding of their role in synapse formation, maturation, efficacy, and plasticity.

As the knowledge of the morphology and functionality of astrocytes has expanded, researchers have acknowledged that the size, complexity, and capabilities of astrocytes have been significantly underestimated. Furthermore, studies evaluating the similarities and differences between human astrocytes and those of experimental animals have exposed the potential importance of astrocyte function in complex brain processing such as learning and memory. Studying the differences between the human brain and those of other mammals is important for understanding the unique computational power of the human brain.[9]

Learning at the Cellular Level

Learning occurs when neurons grow new connections or strengthen existing synapses. Strengthening synapses is fundamental to learning new information. When incoming information reaches the synapse, neurotransmitters are released and bind to receptors in the nerve cell. This process triggers neurons to pass on the information to the next cell. Most traditional studies for the neural bases of learning and memory focus on how neurons transmit information, and how they change to reflect learning. However, recent studies suggest that glia, especially astrocytes, may directly contribute to certain learning mechanisms.[1]

Functions of Astrocytes

Research on new functions of astrocytes has emerged in recent years. New discovers have shown that astrocytes are involved in the regulation of blood flow, the growth of stem cells, as well as synaptic transmission. Although astrocytes are electrically non-excitable cells, they still play a role in neural signaling. Recent studies have shown that communication exists between glia and neurons at the synapse. Presynaptic neurons release neurotransmitters that cause Ca2+ concentration to increase in surrounding glia. Activated astrocytes respond to surrounding neuron activity and the increase in Ca2+ concentration by releasing glutamate, serine and ATP, and other gliotransmitters. In turn, these gliotransmitters respond by enhancing or depressing the release of more neurotransmitters in the presynaptic terminal. Furthermore, transmitters released from glia can directly stimulate postsynaptic neurons by producing excitatory or inhibitory responses. By releasing transmitters, activated through the increase of Ca2+ concentrations, astrocytes modulate the activity of both glial and neuronal neighboring cells.[7]

Recent Studies

[5] Henneberger and colleagues' single-cell experiments1 demonstrate that a rise in astrocyte intracellular Ca2+ controls the induction of long-term potentiation (LTP) at nearby synapses. The authors induce LTP at hippocampal synapses using high-frequency stimulation (HFS). With a pipette, they load individual astrocytes with a control solution (top cell) or a buffer that prevents an increase in intracellular Ca2+ (bottom 'clamped' cell). After HFS, intracellular Ca2+ levels increase in the top astrocyte, which releases D-serine. D-Serine binds to NMDA receptors to promote LTP establishment when glutamate is released from the presynaptic terminal. Preventing the rise in intracellular Ca2+ in the bottom astrocyte abolishes D-serine release and prevents LTP establishment in its territory, but does not affect LTP in the top astrocyte's domain provided that the two cells are at least 200 μm apart.

Role in glutamate regulation

Astrocytes regulate the glutamate transmitter, which is an excitatory, activating receptor that tends to increase the likelihood of the postsynaptic neuron firing. They affect synapses’ ability to strengthen by communicating with downstream neurons to regulate glutamate in the synaptic gap through glial glutamate transporters. This communication between astrocytes and neurons was discovered by examining signaling molecule ephrinA3 and its binding partner EphA4 in mice. It was found that astrocytes promote the development of synapses through the interaction of ephrinA3 and EphA4. Furthermore, findings revealed that the interaction between ephrinA3 and EphA4 also influences astrocytes. If a neuron has a deficit in EphA4 receptors, astrocytes increase the number of transporters in the synaptic gap, which results in the removal of so much glutamate that the strengthening of the synapse becomes impossible.[1]

Role in the increase of neuronal calcium

Advancements in experimental methods and imaging techniques have shown that astrocytes communicate through calcium signaling. Although the concentration of calcium around a cell cannot initiate neural signaling, it can potentially change the chance of a neuron firing, the speed at which a neuron fires, or the size and strength of the connection between two neurons. Using stimuli to raise astrocyte calcium levels, it has been found that astrocytes cause glutamate-dependent increases in neuronal calcium. The elevation in calcium has also been discovered to cause a calcium-dependent release of glutamate. When glutamate is released at synaptic terminals it has the potential to evoke a calcium wave in an astrocytes network. Neurons may stimulate surrounding astrocytes to release glutamate, which feeds back to signal the neuron. Based on these observations, astrocytes not only facilitate fast synaptic transmission, but also regulate glutamates role in synaptic plasticity. Similar to the finding in the previous study, when excess glutamate is released, neuronal damage and degeneration can occur. Therefore, astrocyte-mediated glutamate release and calcium regulation is important in facilitating neuron functioning.[2,10]

Role in D-serine regulation and age-associated deficits in learning and memory

Age-associated deficits in learning and memory can be linked to impairments in synaptic plasticity. Long-term potentiation (LTP) is a form of synaptic plasticity that depends on calcium and is considered the fundamental neuronal activity underlying the formation of memories. During aging, deficits in learning and memory occur along with changes in the threshold and magnitude of LTP. Because astrocytes lack the electrical activity of neurons, their contribution to the process of long-term potentiation was never really considered. However, by studying LTP in hippocampus slices, it has been discovered that the glial-derived neuromodulator D-serine is needed for the induction of synaptic plasticity. Further, the amount of D-serine and its enzyme serine racemase are significantly decreased in the hippocampus during aging. Old rats with impaired LTP given exogenous D-serine were able to recover damaged LTP. This suggests that astrocytes play a significant role in regulating synaptic transmission. Through the availability of the neuromodulator D-serine, astrocytes influence the functional deficits caused by aging.[6]

Unique Features of Human Astrocytes

[4] The size of astrocytes increases with increasing complexity of brain function.

One of the most distinct aspects of the human brain is the complexity and diversity of cortical astrocytes. Human astrocytes are larger, more complex, and more abundant compared to the astrocytes of infaprimate mammals. Because of the significant differences in astrocytes between humans, nonhuman primates, and rodents, researchers propose that the complexity in the structure and function of astrocytes has evolved with the evolution of the human cortical. The evolution of astrocytes reflects their enhanced roles in synaptic modulation and cortical circuitry.[8,9]

Diversity of Human Astrocytes

Human cortical astrocytes have high cortical glial fibrillary acidic protein-positive (GAFP+) expression. At least four major morphologic subclasses of GAFP+ immunoreactive cells have been found in the adult human temporal lobe. The four subclasses include interlaminar, protoplasmic, polarized, and fibrous astrocytes. Chimpanzees also have four subclasses of GAFP+ cells, however, these cells are much less complex than those in the human brain. The cortex of rhesus macaque and squirrel monkeys contain three subtypes of astrocytes, and the cortex of rodents contains only two (protoplasmic and fibrous).[8]

Protoplasmic Astrocytes

[4] Classes of human astrocytes are located within different layers of the cortex. Primate-specific interlaminar astrocytes (light blue) are located in layer 1 and send long fibers that extend throughout the cortex terminating in layers 3 and 4. Protoplasmic astrocytes (dark blue) characteristically inhabit layers 2–6 and vary in size (shown here in layers 2 and 4). Protoplasmic astrocytes are organized into domains associated with neurons and blood vessels (red). Polarized astrocytes (pink) also extend long processes, but are found in layers 5–6 rather than near the pia and have varicosities along their processes (inset). Fibrous astrocytes (green) reside in the white matter (WM) and are not organized into domains.

Protoplasmic astrocytes are the most abundant type of astrocytes in humans and are located in cortical layers 2-6. Human protoplasmic astrocytes are larger, more complex, and more symmetric than those in rats. Most of the GAFP+ processes of protoplasmic astrocytes do not overlap, which indicates the cells are organized in domains.[8]

Interlaminar Astrocytes

Interlaminar astrocytes are primate specific cells and are found in layer 1of the primate cortex. Although these cells are found in nonhuman primates, the morphology of these astrocytes in humans is different. Human interlaminar astrocytes have small spheroid cell bodies and have a thick network of GFAP fibers not seen in primates. The interlaminar fibers violate the domain organization and may be used for long-distance signaling and communication within cortical columns. The functional significance of these cells is still unknown. It has been found that interlaminar fibers are altered in pathologies including Down’s syndrome and Alzheimer’s disease, in which number of interlaminar processes decreases.[8]

Polarized Astrocytes

Polarized astrocytes are also primate specific cells and are located in the deep layers of the cortex near the white matter. These cells are relatively uncommon. Similar to interlaminar astrocytes, polarized astrocytes also do not respect domain boundaries and may provide an alternative pathway for long distance communication across cortical layers, forming links between white and gray matter.[8]

Fibrous Astrocytes

Fibrous astrocytes are located in the white matter and are the least distinguishable between primate and non-primates. Fibrous astrocytes have fewer GAFP+ processes and are less complex than protoplasmic astrocytes. Because of their morphological simplicity, the functions of fibrous astrocytes may by limited to metabolic support. Their role most likely does not extend to the processing and regulation of neural activity.[8]

Study of mice engrafted with human glia

To study the structural complexity and distinct features of human astrocytes, human glial progenitor cells (GPCs) were engrafted into immunodeficent mice to examine the properties of human glia. This resulted in a widespread integration of human glia in the brain of the mice. After the mice had matured, human cells had replaced a significant proportion of their forebrain glia. Due to the presence of human glia, LTP, learning, object location memory, and contextual and tone fear conditioning were all enhanced in the mice. The mice that were allografted with murine GPCs displayed no improvement in LTP or learning. The study demonstrates that human astrocytes generated in mice brains maintain their complex morphology and Ca2+ wave characteristics typical in the human brain. These finding show that human glia enhances learning in mice. Furthermore, it suggests that aspects human cognition and the evolution of human neural processing may be a reflection of astrocytic evolution.[3]

Areas for Further Study

Despite recent advances and research on the role of astrocytes, much more works needs to be done in order to fully understand the function of astrocytes in learning and memory. A major challenge for this field is understanding how astrocytes communicate with each other and with neurons during development in order to establish astrocytic and neuronal network structures. Learning more about the functions of each of the different types of astrocytes will also provide a better understanding of the morphology and functionality of astrocytes and their role in synaptic transmission, neural functioning, and other processes such as learning and memory. The recent studies are only the beginning to the research and investigation of this field.

References

1. Alessandro Filosa, Sónia Paixão, Silke D. Honsek, Maria A. Carmona, Lore Becker, Berend Feddersen, Louise Gaitanos, York Rudhard, Ralf Schoepfer, Thomas Klopstock, Klas Kullander, Christine R. Rose, Elena B. Pasquale, Rüdiger Klein. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neuroscience 2009 September.Max Planck Institute of Neurobiology in Martinsried.

2. Bains , J. S., & Oliet, S. H. (2007). Glia: they make your memories stick!. Trends in Neurosciences, 30(8), 417-424.

3. Han, X., Chen, M., Wang, F., Windrem, M., Wang, S., Shanz, S., Xu, Q., et al. (2013). Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell stem cell, 12(3), 342–53. doi:10.1016/j.stem.2012.12.015

4. Kimelberg, H. K., & Nedergaard, M. (2010). Functions of astrocytes and their potential as therapeutic targets.Neurotherapeutics, 7(4), 338-353.

5. Matsui, T., Unno, M., & Ikeda-Saito, M. (2010). Astrocytes as aide-mémoires. Neuroscience,43(2), 240-247.

6. Mothet , J. P., Rouaud, E., Sinet, P. M., Potier, B., Jouvenceau, A., Dutar, P., Videau, C., & Epelbaum, J. (2006). A critical role for the glial-derived neuromodulator d -serine in the age-related deficits of cellular mechanisms of learning and memory.Aging Cell, 5(3), 267-274.

7. Newman, E. A. (2003). New roles for astrocytes: Regulation of synaptic transmission eric. Trends in Neurosciences, 26(10), 536-542.

8. Oberheim, N. A., Wang, X., Goldman, S., & Nedergaard, M. (2006). Astrocytic complexity distinguishes the human brain. Trends in Neurosciences, 29(10), 547-553.

9. Oberheim, Nancy Ann, Goldman, Steven A, & Nedergaard, Maiken. (2012). Heterogeneity of Astrocytic Form and Function. National Institute of Health, 814, 23-45.

10. Parpura , V., Basarsky, T. A., Liu, F., Jeftiniji, K., Jefiniji, S., & Haydon, P. G. (1994). Glutamate-mediated astrocyte-neuron signaling. Letters to Nature, 369, 744-747.

Click picture links for references.