Glial cells enabled mammals increasing speed of reaction and more complex brain func- tions. As animals became more complex, there was an increase in the glial cell to neu- ron ratio. Astrocytic processes are intimately associated with synapses and blood vessels and form the blood–brain barrier, as well as controlling potassium homeostasis and the uptake of cellular waste after brain insults. Astrocytes have receptors for the principal neurotransmitters (glutamate and GABA), hence the name tripartite synapse [17].
The increased ratio of glial cells to neurons observed in animal brains went further in humans, with a glial cell to neuron ratio of about 6:1 (~85 percent versus 15 per- cent). In humans there are more glial cells in the prefrontal cortex than there are in any other animals apart from cetaceans. Certain parts of tertiary association areas such as the inferior parietal cortex may be cytologically different. For example, Einstein’s brain revealed a two fold increase in glial cell to neuron ratio in the inferior parietal lobule, compared to the human norm established from 11 male controls [18]. Nansen specu- lated that glial cells may be a factor in superior intellectual ability. Anatomical dissection of Einstein’s brain revealed that the left inferior parietal lobe was also larger than the right, and the right superior parietal lobe larger than the left, together with expanded prefrontal cortices (compared to 25 human control brains). Interestingly, these brain components increased in size during hominin evolution and also showed considerable reorganization [19].
Table 4.1 Brain vital statistics Brain
Neurons 1011 (100 billion)
Glia 1012 (1 trillion)
Synapses 1015 (1 quadrillion)
Connectome 150 000 km of axons
Blood vessels 700 km
One mm3 brain comprises
Neurons 50 000
Synapses 50 × 106
Dendrites 150 m
Axons 100 m
All our cells 1013 (10 trillion)
Microbiome
Microbes 2 × 1014 (200 trillion)
Microbiome 1.5 kg
Neurophysiology
Human sensory systems receive ~11 million bits of information per second Conscious mind processing capability ~16–50 bits per second
Conscious activity ~5 percent of all cognition
Non-conscious activity ~95 percent of processing
Neurochemistry, energy consumption
Action potentials energy 47 percent
Postsynaptic processing 34 percent
Resting neuronal potential 13 percent
Glutamate recycling 3 percent
Source: data from [13–15].
Brain Processing Dimensions in 3D Space and Time 73
Astrocyte Complexity and the Concept of the Glioneuronal Unit
Glial cells form astroglial networks and communicate with neurons and capillaries through the tripartite synapse [20]. In essence, they eavesdrop on neuronal signaling and have their own neurotransmitter receptors, which allows glia to furnish the brain with additional dimensions in information processing. A single astrocyte can envelop and influence approximately two million synapses and incorporate large groups of synapses and neurons into functional units [21].
This provides a prodigious increase in flexibility and power of information processing over and above synaptic strength modification of individual synapses within neural cir- cuits. The expansive domains of operation of glia through chemical cellular transmission diffuses widely and can transgress the hardwired tracts of neuronal connections. This enables a more global scale of information processing compared to the point-to-point synapse- based neuronal systems. A useful analogy is to think of this as “the brain’s spe- cial kind of internet system.” Furthermore, the global glial communication networks also coordinate immunological, hormonal, and vascular networks.
In the study of mice by Tremblay et al., sensory experience was seen to alter the microglial–synaptic interactions. They interpreted these results as implying that micro- glia, in addition to their known role in immune surveillance in the brain, may play an active role in bestowing experience- dependent alteration of synapses as well as elimina- tion of some synapses as part of their function in health. These functions contribute to learning and memory. These findings indicate a more complex arrangement than the tripartite synapses, involving the neuron, the glial cell, and capillary. With the addition of the microglial component often intricately associated with the tripartite synapses, a more appropriate term would be the quadripartite synapse (Figure 4.1) [22].
The glial to neuron cell ratio in humans is 1.65 compared to Pan troglodytes’ 1.20 in layer two/three of the prefrontal cortex. Axon length increases accompanying brain enlarge- ment and the concomitant energy required to fire a spike increased, therefore consuming more ATP by a factor of 3.3 in humans compared to rats [23]. Hence glia proliferate to support the increased metabolic demand of larger cortices in humans and the neurons with long- range axons are more susceptible to neurodegeneration and dementia [24].
(a) (b) (c)
Figure 4.1 Microglial processes in health and disease: quadripartite rather than tripartite. A synapse between an axon terminal (blue) and dendritic spine (pink) contacted by an astrocyte (green) and microglial cell (taupe).
Engulfment by a microglial process of an intact synapse between an axon terminal and a dendritic spine. This supports a microglial phagocytosis (ingestion) of synapse components that may be relevant to plasticity in the brain.
Source: Tremblay ME, Majewska AK. A role for microglia in synaptic plasticity? Commun Integr Biol 2011;4:220–
222. Reproduced with permission of Taylor & Francis Ltd, www.tandfonline.com
Astrocytic Complexity of the Human Brain
Several different astrocyte subtypes have been discovered in the human brain thus far.
These include human protoplasmic astrocytes (HPA), human intralaminar astrocytes (HIA), human polarized astrocytes (HPoA), and human fibrous astrocytes (HFA). The HPA are the most abundant and reside in layers 2–6, can monitor five microcapillar- ies, and have a large number of gap junctions composed of connexin that link processes within the cell. Comparative data between humans and rodent HPA are notable for the human cell having an approximate tenfold increase in processes radiating from the HPA cell, a feature that allows these cells to modulate approximately two million synapses. The HIA cells are thought to be specific to primates, occur in layer one of the cortex, which lacks neurons, and have exceptionally long, often unbranched extensions that traverse the cortex, usually terminating in layers three and four. The HPoA reside in the deeper part of the cortex, with processes containing numerous varicosities. The HFA occur in the white matter and have less glial fibrillary acidic protein (GFAP) containing processes and are thought to have primarily metabolic support functions (Figure 4.2).
Functions of astrocytes therefore include vascular effects, with blood flow regula- tion and blood–brain barrier maintenance, water and ion homeostasis, neurotransmitter production and removal, stem cell proliferation, and determination of synaptic num- ber. Astrocytic domains have been identified in areas known to have a lot of synapses, such as the hippocampus, underscoring their role as synaptic transmission modulators.
Astrocytes can also discern neuronal activity that may induce the release of gliotransmit- ters. This neurochemical interaction has created an additional dimension of communica- tion involved in the processing of what has been termed “activity independent of synaptic transmission.” Through these astrocytes and the increasing complexity and formation of the glioneuronal functional unit, integration of and control over larger sets of contiguous synaptic sets are possible. In this fashion, the glioneuronal functional unit augmented the human brain’s processing power to surpass most, if not all other species [25].
Hence, increased connectivity has occurred at a cellular or molecular level as well as at a connectomal level. Glial cells are increasingly being implicated in almost all neurologi- cal disorders, including, stroke, dementia, migraine, and epilepsy by way of mechanisms involved with blood flow regulation, cell signaling, oxidative stress, inflammation, and apoptosis [26].