Housekeeping cells in the brain driving schizophrenia

By Andrea Flores Esparza

The brain can be viewed as a theatrical performance, where the neurons are the protagonists on the play whilst glial cells are the backstage crew that ensure that the show runs smoothly (BrainFacts, n.d.). Although neurons are considered the basic working unit of the brain due to their fascinating ability to propagate action potentials for the transmission of information across the nervous system, their performance depends heavily on glial cells. The term “glía” originates from the Greek and translates to “glue” in English, alluding to their supportive role in the nervous system (Jäkel & Dimou, 2021). Glial cells, also known as ‘glia’ or ‘neuroglia’, are non-neurological cells of the central and peripheral nervous system that facilitate the work of neurons as these maintain homeostasis, generate myelin for insulation as well as providing protection. Although there is continuous debate on the exact number of glial cells and their abundance, it is believed that these outnumber neurons in a ratio ranging between 3 to 10 glial cells per neurons in mammals (Brainfacts, n.d.; Purves et al., 2001). 

But what exactly are glial cells and why are they so important? Before addressing this, it is important to clarify that glia is an umbrella term for non-neurological cells, and thus consists of four subtypes: microglial cells, astrocytes, oligodendrocytes and Schwann cells (Purves et al., 2001). In short, microglial cells are the specialised tissue-specific macrophages of the central nervous system (CNS) (Yin et al., 2017). These cells are considered to be the nurses of CNS as they provide primary immunity and protection due to their underlying ability to phagocytose pathogens (BrainFacts, n.d.). Astrocytes, being the most abundant type of macroglia in adult brains, undertake a wide range of essential roles in the CNS (Jäkel & Dimou, 2021). These cells are responsible for maintaining the chemical environment in the brain, regulating the filtering of molecules into the brain tissue as part of blood brain barrier (BBB) as well as controlling ionic and water homeostasis (BrainFacts, n.d.), (Yim et al., 2019). Astrocytes are also responsible for the preservation of synapse well-being by forming/eliminating synapses, recycling neurotransmitters and provide support and ensuring adequate blood flow to neurons (BrainFacts, n.d.; Yim et al., 2019). Lastly, oligodendrocytes and Schwann cells are both responsible for forming the insulating myelin sheath around the axons for the neurons in the nervous system. This insulating layer composed of protein and fatty substances enables a faster and more efficient propagation of action potentials (A.D.A.M inc., n.d.). The difference between these two cells lies on the fact that oligodendrocytes are responsible for myelinating neurons in the CNS whilst Schwann cells are responsible for the ones in the peripheral nervous system (PNS) (Jana et al., 2008). The modulating role of neurodevelopment and homeostasis of glia has raised numerous questions on the impact of their faultiness on brain function and disorders.

Research on the role of flawed glia on mental disorders over the years has proposed numerous hypothesis aiming to explain the underlying cause and progression of these. One of the focal points of these research studies has been on schizophrenia, a chronic mental disorder affecting approximately 1% of people world wide (MentalHelp, n.d.). Schizophrenia involves a series of episodes in which the affected individual is unable to differentiate between real and unreal experiences. According to the American Psychiatric Association (ASA) (Torres, n.d.), the frequency, severity and duration episodes vary greatly and compromise various different symptoms. The three distinct episodes that a schizophrenic person may experience include those with positive, negative and/or disorganised symptoms. Positive symptoms include hallucinations, delusions, paranoia and exaggerated behaviours; whilst negative symptoms include loss of motivation and depression. Lastly, disorganised symptoms refer to those when an individual is utterly confused and thus has trouble thinking and behaving logically (Torres, n.d.). The multifactorial nature of the disease, including genetic, histopathological and environmental influences has made it very challenging to understand schizophrenia (Dietz, Goldman & Nedergaard, 2020). Recent experimental work has suggested that the onset and development of schizophrenia does not only rely on neuronal dysfunction but may also be heavily influenced by abnormalities in glial cells (Dietz, Goldman & Nedergaard, 2020; Wang, Aleksic & Ozaki, 2015). However, the contribution of glial cells on the etiopathology of schizophrenia remains unclear.

Andrea G Dietz et al., propose that the defective differentiation of glial progenitors influenced by the immune activation of microglia may contribute to the dysfunctional mechanisms in schizophrenia (Dietz, Goldman & Nedergaard, 2020). In their review, they suggest that activation of microglia during embryogenesis induces cytokine release and neuroinflammation, which in turn negatively affects the ability of glial progenitors to differentiate.  They explore the notion that faulty differentiation of glial progenitors into oligodendrocytes and astrocytes contribute to the desynchronised and abnormal brain activity seen in schizophrenia. Faulty oligodendrocytes and astrocytes would thus lead to the hypomyelination of neurons as well as deregulated homeostasis and synaptogenesis respectively. 

Analysed from another perspective, Chenyao Wang, et al. explore the potential role of glia-related genes in the development of schizophrenia (Wang, Aleksic & Ozaki, 2015). According to their publication, the evidence strongly suggests that oligodendrocyte hypoplasia and abnormal gene expression of oligodendrocyte-related genes may be associated with aberrant white matter integrity, a characteristic commonly observed in schizophrenia. Since white matter is mainly composed of myelinated axons, would be heavily impacted with oligodendrocyte abnormalities, resulting in a dysfunctional transmission network. For instance, down-regulation of the oligodendrocyte-related genes OLIG1, OLIG2 and SOX10 have been frequently observed in schizophrenia, alluding to the genetic element of the disease. Interestingly, the authors provide a strong argument for the role of abnormal oligodendrocytes and schizophrenia when explaining that myelination processes during the postnatal period are accomplished during the same period of time as schizophrenia onsets. Moreover, Chenyao Wang et al., also address the neurotransmitter hypothesis of schizophrenia—stating that hyperactive transmission of dopamine results in schizophrenic symptoms (Wang, Aleksic & Ozaki, 2015)— by associating it with abnormalities in astrocyte-related genes as these cells are essential for synaptic metabolism. 

Despite the strong evidence suggesting a role of glial cells in the development of schizophrenia, it is important to bear in mind the heterogeneous entity of the disorder as it cannot be simplified to dysfunctional glia. Thus, a multifactorial approach is required to understand the complexities of this disorder in order to provide adequate and effective treatment to patients. This is not only true for schizophrenia, but to the understanding of brain functions as a whole. Nonetheless, the potential of glia-based research approaches may be able to provide a fascinating insight to deepen the understanding of schizophrenia.

References:

BrainFacts.org. “Brain Awareness Video Contest: Neuroglia and the Brain”. Available from: https://www.youtube.com/watch?v=8T5kDS4jE1Y 

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Jäkel S and Dimou L. “Glial Cells and Their Function in the Adult Brain: A Journey through the History of their Ablation”. Frontiers in Cellular Neuroscience. 2017. 11:24. Available from: https://doi.org/10.3389/fncel.2017.00024

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Purves D, Augustine GJ, Fitzpatrick D, et al., editors. “Neuroglial Cells”. Neuroscience 2nd edition. 2001. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10869/ 

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Jana M, Dasgupta S, Ghorpade A and Pahan K. “Astrocytes, Oligodendrocytes and Schwann Cells”. Neuroimmune Pharmacology. 2008. 69-88. Available from: https://doi.org/10.1007/978-0-387-72573-4_8 

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MentalHelp. “Schizophrenia Symptoms, Patterns and Statistics and Patterns”. MentalHelp.net. Available from: https://www.mentalhelp.net/schizophrenia/statistics/

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Dietz AG, Goldman SA and Nedergaard M. “Glial cells in schizophrenia: a unified hypothesis”. The Lancet Psychiatry. 2020. 7(3); 272-281. Available from: https://doi.org/10.1016/S2215-0366(19)30302-5

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Wang C, Aleksic B and Ozaki N. “Glia-related genes and their contribution to schizophrenia”. Psychiatry and Clinical Neurosciences. 2015. 6(8). Available from: https://doi.org/10.1111/pcn.12290

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