Axol Bioscience Science Scholarship recipient, Nataly Martynyuk, is a PhD student at the Brain Repair Centre, Department of Clinical Neurosciences, University of Cambridge, UK. Her research focuses on the actions of alpha-chimerins in mechanisms relevant to dendritic spine formation and neurodegeneration. Nataly reviews the evolution of astrocyte research, their biological form and function, and the role they play in human consciousness and memory formation.
The binding problem
Recently, neuroscience has provided some exciting progress in unraveling an age-old mystery of consciousness by providing ways to measure properties of neurons. However, this approach soon faced an obstacle called the binding problem, or lack of a neuronal substrate that would combine all information from numerous highly specialized neuronal areas into a seamless, succinct picture of the world we are all internally familiar with. Some theories proposed the existence of neuronal circuits storing memory in their particular arrangements (1–3). But who is the puppeteer arranging these connections?
There is a tessellated interconnected net of highly complex cells embracing the entire human nervous system. These cells, unlike neurons that show no significant differences in their morphology or electrical properties among mammals (4–6), develop to their peak in humans (4,7), and are noted to have had particularly large processes in the brain of Albert Einstein (8). These cells orchestrate neuronal positioning and synaptic strength, which is thought to be the basis of memory and intelligence (9–13). And yet only few studies explored their role in consciousness up to date.
Glial glue: not what it says on the tin
Since the discovery of neurons as an important part of the brain in 1740 (14,15), it has been observed that they co-exist side-by-side with their neighbors with an unfortunate umbrella- name ‘glia’ meaning ‘glue’. Although even Cajal noted that some star-shaped cells, or astrocytes, are more prominent in humans, which is likely to have a physiological significance (16), their functions and properties were largely unknown and deemed to be limited to supporting neurons. This ‘glia’ misnomer is still widespread today, even though modern techniques demonstrate that glial cells such as astrocytes and oligodendrocytes are as different from each other as they are from neurons (17). Astrocytes, the ‘star-shaped’ cells, represent the most numerous glial type in mammalian brains with a recently discovered heterogeneity and complexity in structure and function (18,19). They do not exhibit action potentials, but rather propagate calcium waves via interconnecting gap junctions, as well as release and respond to chemical transmitters they often share with neurons, which can exert both excitatory and inhibitory effects on neuronal connections depending on the context (9,20–22). Let us examine their path to such a prominent position.
Evolution of the astrocyte
In evolutionary terms, astrocytes represent a newer invention compared to neurons. Certain animals like hydras and jellyfish rely only on their diffuse nervous systems. Primary glial cells that could share astrocytic features emerge from the same ectodermal origin as neurons alongside nervous system centralization in the earliest bilateral animals - Acoelomorpha flat worms (23). It appears that astrocyte-like cells direct and organize nervous centers throughout evolution, with increasing complexity of neuronal masses being accompanied by development and elaboration of respective astroglia. An interesting example of this trend is brains of elasmobranchs such as sharks and rays. These fish, with intelligence comparable to that of some mammals (24), possess two types of brains: the thinner laminar and thicker elaborated ones. While laminar brains contain only a thin layer of neurons, which cease to migrate far from the neurogenic zones in ventricles and simpler glial types with some astrocytic features, elaborated brains comprise neuronal nuclei alongside multiple astrocytes (23,25). Similarly, in mammals an increase in brain complexity and computational power follows astroglial complexity development (4,23,26).
This evolutionary path is partially recapitulated during organismal development. Although neurons and astrocytes share the parent stem cell type (27,28), neurons are already present at 55 days in utero in humans, while astrocytes take several weeks to mature from neural stem cells extracted at this stage (author’s data). Astrocytes ensure that neurons migrate to their correct locations and form contacts with the appropriate targets (27), and this function persists throughout adulthood (5,11,12).
The human brain possesses an unprecedented power of self-reflection and memory in the animal kingdom. While studies comparing relative brain sizes, neuronal types, electrophysiology, and cortical lamination fail to comprehensively explain the origin of consciousness (4–6), neocortex evolution is proposed to involve “largely mysterious…changes in neurogenesis, migration and axon guidance” (13). In accordance with this, astrocytes, which play a role in all of the named processes, present some uniquely hominid features in humans and higher primates, with the peak complexity in humans (Fig. 2).
Interlaminar and varicose projection astrocytes
The higher primates like humans and chimpanzees have two morphological types of astrocytes, which are absent in other species: interlaminar and varicose projection (or polarized) (4,7,29). Interlaminar astrocytes inhabit the top cortical layer, or layer 1, which is lacking neuronal cell bodies and mostly contains synapses. Their shorter processes create a dense network near the pia, while the longer processes extend down through several cortical layers for up to 1 mm and end with a terminal mass enriched in mitochondria (4,30). It is these interlaminar processes that were particularly large in Einstein’s brain (8), increase in length and number from childhood to adult states (31), and get affected in human brain pathologies like Down’s syndrome and Alzheimer’s disease (32,33). Varicose projection astrocytes also send processes up to a millimeter in length; however, they tend to reside in deeper areas of the cortex in layers 5-6. As their name suggests, their unique processes contain small varicosities every 1 µm (4,7). These long processes of both astrocytic types contact multiple cells as well as vasculature, and may serve as non-neuronal pathways of long-distance communication and integration.
Protoplasmic and fibrous astrocytes
The other two types of astroglia, protoplasmic and fibrous astrocytes, are more common among mammals. Nonetheless, human cells are found to be far from identical to those of experimental animals such as mice and rats. Protoplasmic astrocytes abundantly populate cortical layers 2-6, representing the most common astrocytic type. Unlike other astrocytes, these cells present a cloud, 100-200 µm in diameter in humans, of relatively short bulbous processes around the cell body (4,7). These processes of a single cell, together with synapses they embrace, define an astrocytic domain. They also actively interact with the brain vasculature and contribute to the blood-brain barrier formation (4). While the synaptic density in rats is slightly higher than in humans (6), the size of such astrocytic domains is disproportionally increased in the human brain. Human protoplasmic astrocytes extend ten times more processes, exhibit a 2.55-fold increase in diameter, a 27-fold increase in volume, and a more than 20-fold increase in the number of interacting synapses in comparison with their respective rodent counterparts (4,7) (Fig. 3). Functionally, human astrocytes transmit calcium signals at least 5 times more rapidly than those in mice (7). Interestingly, protoplasmic astrocytes do not share the territories they reign. They are spaced evenly throughout the cortex with only 4.6% of a particular astrocytic domain volume being shared with its neighbour in mice (34). Fibrous astrocytes are located in the white matter and lack domain organisation. These cells show the least number of differences between species, albeit their size being increased in humans (7). Since the white matter lacks synapses, astrocytes residing in this area represent the most simple and homogenous type, which is likely to fulfil its traditionally ascribed role of metabolic support.
Astrocyte complexity and memory formation
There is some exciting evidence that increased astrocyte number and complexity corresponds to increased information processing and storage. In addition to the evolutionary studies, ontogenesis examination points in the same direction. For instance, neuronal numbers are attained at birth, and synaptic pruning constitutes an important part of brain maturation (35,36). In contrast, astroglial differentiation enhances with development and contributes to brain growth (37). Moreover, an enriched environment provokes a rise in astrocyte/neuron ratio beneficial for the nervous system regeneration (38,39). However, until recently, no studies could resolve a problem of correlation not necessarily implying causation. Two prominent publications in Cell shed some light on this issue. In 2013, Han and colleagues managed to substitute a large population of astrocytes in the mouse brain with human cells (40). In their study, human glial progenitors successfully integrated in the host and formed functional gap junctions with indigenous rodent astrocytes, while maintaining their human size and complexity. The resulting chimaeric mice outperformed their littermates in a range of memory tests, including Barnes maze navigation and object-location memory.
In addition, long-term potentiation at synapses in the hippocampus, which serves as a marker of memory formation, was intensified. This study, albeit elegant and convincing, does not compare the effects of astrocytes to those of neurons on memory formation. A good example of a paper that provides such comparison is a 2012 publication that investigates roles of astroglial and neuronal cannabinoid receptors in memory impairment (41). Even though neurons with the absent CB1 receptors still show signs of long-term depression in the mouse hippocampus following an exposure to exogenous cannabinoids, deletion of the astrocytic CB1 receptors completely abolishes cannabinoid-mediated synaptic weakening. This highlights the importance of astrocytes in the normal synaptic homeostasis and memory storage.
Neurocentric vs astrocentric
It is reasonable to ask why brain science was neurocentric for so long. The very name ‘nervous system’ shows a biased view of the brain cell hierarchy. The main explanation is that neurons have an easily recognisable morphology and provide anatomically obvious means of communication between the brain and the outside world. This led to a blossoming of the neuron theory in the 19th century (15) alongside development of appropriate imaging techniques. Additionally, neurons offer a simple and discrete output in the form of action potentials. Hodgkin and Huxley conducted their ground-breaking electrophysiology experiments, which allowed them to tap into the mechanisms of action potential generation, for which they won a Nobel prize in 1963. In contrast, we are only at the dawn of a technique development that would allow us to understand subtler functions of astrocytes. While our understanding of neuronal morphology has hardly progressed since Cajal, it turns out that astrocytes are much more complicated than first thought. An intermediate filament called glial fibrillary acidic protein (GFAP), which was long assumed to be the marker of cells of astroglial lineage, proves to occupy only 15% of the total astrocyte volume (34) (Fig. 3). Only relatively recent studies attempted to use diolistic labelling to categorise astrocytic morphology (4,7). Furthermore, subsets of GFAP-negative astrocytes have been discovered (42), making researchers reconsider the use of cell markers and terminology.
Importantly, because neurons have similar properties in humans and common experimental animals such as rodents, Drosophila, or C. elegans, while astrocytes show a greater difference, exploration of the human-specific astrocytic features that might be absent in simpler animals is less trivial. One of the first papers discussing potential glial contribution to neuronal functions was published in 1960 (43), which for the first time proposed that glia might indeed support neurons, but “in addition it would somehow ‘tell’ the neuronal masses what they are supposed to do”, offering a comparison to a computer program that commands its digital units to follow specific instructions. Potentially, development of a computer technology was pivotal in this mental shift, allowing to regard neurons as wires and hardware, and astrocytic tessellations as a higher-order software making sense of the neuronal input. The astrocentric hypothesis of consciousness was therefore proposed by Robertson, and reviewed by Crick among others, in the early 21st century (44). There is a great potential that future experiments will provide it with more support.
Therapeutic significance of astrocyte research
Other than answering philosophical questions regarding the nature of consciousness, astrocyte research has practical therapeutic significance. Braak and colleagues observed an alpha- synuclein immunoreactivity in astrocytes that progresses in accordance with the neuronal pathology in Parkinson’s disease (45); astrocytes display metabolic and morphologic alterations in beta-amyloid and tau pathologies such as Alzheimer’s disease (33,46,47), as well as in Down’s syndrome (32,48) and schizophrenia (49) to give a few examples. There is a possibility that the astrocytic pathology is not a bystander or a passive consequence, but rather an active player in some or all of these disorders, so that understanding the astroglial pathology or astrocyte neuroprotective functions could ameliorate the disease progression. Some emerging therapies are indeed addressing this issue. For example, transplanting a subset of astrocytes into the striatum of rats successfully alleviates some pathological changes in a model of Parkinson’s disease (50), providing an alternative to neural transplants.
With no doubt, new technologies will unravel more mysteries of the star-shaped cells. Although many functions of astrocytes are still unknown, new research offers a great promise.
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