Astrocyte Pathology in the Prefrontal Cortex as New Cause of Cognitive Dysfunction?

New research indicates that astrocytes may play a role in cognitive dysfunction (at least in rats). Here is a brief description of astrocytes from Wikipedia:

Astrocytes, also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They are the most abundant cell of the human brain. They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.

Again, from Wikipedia, here is a list of the functions astrocytes perform in the brain:

Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. More recently, the function of astrocytes has been reconsidered,^[3] and are now thought to play a number of active roles in the brain, including the secretion or absorption of neural transmitters and maintenance of the blood–brain barrier.^[4] Following on this idea the concept of a "tripartite synapse" has been proposed, referring to the tight relationship occurring at synapses among a presynaptic element, a postsynaptic element and a glial element.^[5]

• Structural: They are involved in the physical structuring of the brain. Astrocytes get their name because they are "star-shaped". They are the most abundant glial cells in the brain that are closely associated with neuronal synapses. They regulate the transmission of electrical impulses within the brain.
• Glycogen fuel reserve buffer: Astrocytes contain glycogen and are capable of glycogenesis. The astrocytes next to neurons in the frontal cortex and hippocampus store and release glycogen. Thus, Astrocytes can fuel neurons with glucose during periods of high rate of glucose consumption and glucose shortage. Recent research suggests there may be a connection between this activity and exercise.^[6]
• Metabolic support: They provide neurons with nutrients such as lactate.
• Blood–brain barrier: The astrocyte end-feet encircling endothelial cells were thought to aid in the maintenance of the blood–brain barrier, but recent research indicates that they do not play a substantial role; instead, it is the tight junctions and basal lamina of the cerebral endothelial cells that play the most substantial role in maintaining the barrier.^[7] However, it has recently been shown that astrocyte activity is linked to blood flow in the brain, and that this is what is actually being measured in fMRI.^[8][9]
• Transmitter uptake and release: Astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP, and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca²⁺-dependent manner.^[10] (This has been disputed for hippocampal astrocytes.)^[11]
• Regulation of ion concentration in the extracellular space: Astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space.^[12] If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.^[13]
• Modulation of synaptic transmission: In the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons.^[14] In the hippocampus, astrocytes suppress synaptic transmission by releasing ATP, which is hydrolyzed by ectonucliotidases to yield adenosine. Adenosine acts on neuronal adenosine receptors to inhibit synaptic transmission, thereby increasing the dynamic range available for LTP.^[15]
• Vasomodulation: Astrocytes may serve as intermediaries in neuronal regulation of blood flow.^[16]
• Promotion of the myelinating activity of oligodendrocytes: Electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. However, the ATP does not act directly on oligodendrocytes. Instead, it causes astrocytes to secrete cytokine leukemia inhibitory factor (LIF), a regulatory protein that promotes the myelinating activity of oligodendrocytes. This suggest that astrocytes have an executive-coordinating role in the brain.^[17]
• Nervous system repair: Upon injury to nerve cells within the central nervous system, astrocytes fill up the space to form a glial scar, repairing the area and replacing the CNS cells that cannot regenerate.^{[citation needed]}
• Long-term potentiation: Scientists debate whether astrocytes integrate learning and memory in the hippocampus. It is known that glial cells are included in neuronal synapses, but many of the LTP studies are performed on slices, so scientists disagree on whether or not astrocytes have a direct role of modulating synaptic plasticity.

This is an important addition to previous research demonstrating the role of astrocyes in developmental disorders:

• Barker, AJ, Ullian, EM. (2008). New roles for astrocytes in developing synaptic circuits. Communicative & integrative biology; 1(2): 207–11. PMID 19513261. 
• Sloan, SA, Barres, BA. (Mar 29, 2014). Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Current opinion in neurobiology; 27C: 75–81. PMID 24694749.

Here is a summary of the new research, followed by the abstract for the article, which is, of course, hidden behind a paywall.

A new cause of mental disease?

Thursday 24 July 2014
Researched and Written by Catarina Amorim

Astrocytes, the cells that make the background of the brain and support neurons, might be behind mental disorders such as depression and schizophrenia, according to new research by a Portuguese team from the ICVS at the University of Minho. The study, in Molecular Psychiatry, shows how a simple reduction of astrocytes in the prefrontal cortex (which is linked to cognition) can kill its neurons and lead to the cognitive deficits that characterise several mental diseases. Although malfunctioning astrocytes have been found in psychiatric patients before, it was not clear if they were a cause or a consequence of the disease.

"This is the first time that cognitive deficits of a psychiatric illness can be mimicked by solely affecting astrocytes" - says the team leader, João Filipe Oliveira - "opening a whole new range of possibilities, both on the causes and potential treatments for these disorders." The research by Ana Raquel Lima, João Filipe Oliveira and colleagues is particularly significant when we look at the heavy burden in human suffering and financial cost of mental diseases. In the US and Europe about 1 in 4 adults are affected in every given year (this is about 26% of the populations), while depression alone uses almost 5% of the total world health budget. And a new player behind a disease offers also potential new and maybe more effective treatments.

So what are astrocytes? These star-shaped cells are part of the so called "glial population" - non-neuron cells that form the brain background and that for a long time were considered mere "housekeepers" of the real players - the neurons. In fact, traditionally, brain function is the result of electrical impulses passing between neurons, transmitting the information necessary for all those extraordinary abilities of this brains ours, from memory storage and motor control to personality quirks.

But astrocytes, even if believed to be "the help", have always been the subject of much curiosity since it was claimed by some (and denied by others) that one of the few uniqueness of Einstein's brain was larger and more complex astrocytes within its cerebral cortex than "normal" individuals. Equally curious, was the fact that these are the most numerous cells in the mammalian brain, because keeping cells alive costs energy, which is always in short supply, and astrocytes were not even part of the of main action/brain activity. Or so it was thought.

In fact, the last decade has seen our ideas on astrocytes (and glial cells in general) change radically; we now known they perform highly complex jobs, including several previously associated with neurons. They are, for example, important for synapses (the specialised structures that do the contact between different neurons and through which the electrical signal is transmitted), where astrocytes detect and modulate activity, so effectively controlling the transmission of information in the brain.

Supporting their importance in the brain several studies have shown that patients with mental diseases - such as depression, bipolar disorder and schizophrenia - have lower than normal astrocyte density in the brain, especially in the prefrontal cortex. This can be improved, though, with anti-psychotic drugs.

This not only supports the importance of astrocytes in normal brain function, but also suggests they could play a role in mental disorders. And in fact, in one study killing astrocytes in the prefrontal cortex of rats seemed to cause a depression-like behaviour. But even if faulty astrocytes and mental diseases were often seen together, it was not possible to be sure, at least in psychiatric patients, that these cells were behind the disorder.

It is in this state of affairs that Lima and colleagues, in the work now published, decided to design a simple but very effective experiment to understand what was happening.

They start by injecting rats in the prefrontal cortex with a toxin that specifically kills astrocytes in a very localized way, and then tested the animals' cognitive abilities correlating these with the animals' (changed?) brain structure. The prefrontal cortex was chosen because it controls cognitive abilities such as planning, reasoning and problem solving, which are affected not only in the most common mental diseases, but also on age-related neurodegenerative illnesses like Alzheimer's.

As expected toxin-injected animals developed the cognitive deficits typical of mental disorders where the prefrontal cortex is affected. But what was really interesting, were the brain changes found - not only the prefrontal cortex's astrocytes had died with the toxin (as expected) but, as time passed, also did its neurons. Control animals injected with a solution free of toxin had no changes, either in behaviour or brain structure.

So even if faulty astrocytes have been found before in mental patients, the Portuguese researchers' results give robust support to the idea that astrocyte breakdown can be a primordial cause for these disorders (and not a result of them), and also suggests how it occurs. "Until now, we have blamed the poorer performance of the prefrontal cortex in these diseases on the surrounding astrocyte pathology" - says Oliveira - "but this study now supports the view that astrocytes, targeted in a pathological process, may actually lead to neurodegeneration in a specific brain region. Psychiatric disease can be mimicked by simply affecting astrocytes!"

This is a totally new perspective on how these diseases can develop, and consequently on how to treat them. For now, while we do not test other brain areas, Oliveira's results are specially relevant for mood disorders diseases - depression, schizophrenia and bipolarity - which we know to have both loss of cognitive functions, and abnormalities in the astrocytes of the prefrontal cortex.

But Oliveira and his team's findings are also important challenging the still too present view of the brain as a simple network of neurons, clearly showing that we need to see it instead as an interdependent circuit of neural and glial cells (in particular astrocytes) both in health and disease.

The new work also makes us also wonder if the claims on the importance of the astrocytes in Einstein's brain were that crazy after all...

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Full Citation:

Lima, A, Sardinha, VM, Oliveira, AF, Reis, M, Mota, C, Silva, MA, Marques, F, Cerqueira, JJ, Pinto, L, Sousa, N and Oliveira, JF. (2014, Jul). Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats. Molecular Psychiatry; 19, 834-841. doi:10.1038/mp.2013.182

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats

A Lima, V M Sardinha, A F Oliveira, M Reis, C Mota, M A Silva, F Marques, J J Cerqueira, L Pinto, N Sousa and J F Oliveira

Abstract

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron–astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-α-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.