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Shifting Perspectives: Implicating Microglia in the Development of Schizophrenia Pathogenesis

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Schizophrenia is a disorder of high complexity in which many neural pathways present aberrant signaling. ­­­In fact, this is true in the symptoms that are presented as it is arguably one of the most heterogenous disorders, with symptoms ranging from hallucinations to flat affect. As changes in the dopaminergic, serotonergic, cholinergic, glutamatergic, and GABAergic systems are present, not one singular factor has been identified as the root cause. On a more macroscopic scale, structural abnormalities are seen such as decreased brain volumes and enlarged ventricles1. 
            Currently, there is no singular genetic variant or environmental factor in which the development of schizophrenia can be attributed. Rather, the prevailing understanding is that schizophrenia arises through sets of gene by environment interactions over long periods of time. Being that the pathophysiology is so heterogeneous in systems as well as across patients, this variance may be attributed to an accumulation of these interactions over a lifetime. 
            Recent research has pointed to several roles microglia play in driving this pathophysiology1–5. A more recent endeavor in understanding the basis of schizophrenia amongst other disorders, as more studies are published linking the neuroimmune function of these cells to pathology, the conversation and hypothesis surrounding these disorders is being reframed. Microglia, the resident immune macrophage-like cells in the brain oversee much of the processes that remove debris from the brain as well as prune under-active synapses4. As these cells begin their lineage in the yolk sac, they are persistent throughout neural development. Therefore, much research is being done to look at the long-term effects alterations in microglia can have in the brain when affected by genetic and environmental factors. 
            As more and more studies implicate microglia in the development of schizophrenia, this cell type should be included more conversations regarding neuropathology. It is the case that many studies rely only on neuronal genetics, physiology, and morphology where it may be helpful to bring microglial function into the conversation. Overall, the sheer utility of microglia as a cell type is changing many understandings of disorders such as schizophrenia and giving much insight into how they develop.


Works Cited 
1.         Jaaro-Peled, H., Ayhan, Y., Pletnikov, M. V. & Sawa, A. Review of Pathological Hallmarks of Schizophrenia: Comparison of Genetic Models With Patients and Nongenetic Models. Schizophr. Bull. 36, 301–313 (2010).
2.         Wang, M., Zhang, L. & Gage, F. H. Microglia, complement and schizophrenia. Nat. Neurosci. 22, 333–334 (2019).
3.         Tay, T. L. et al. Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan. Front. Mol. Neurosci. 10, (2018).
4.         Nayak, D., Roth, T. L. & McGavern, D. B. Microglia Development and function. Annu. Rev. Immunol.32, 367–402 (2014).
5.         Sellgren, C. M. et al. Increased microglial synapse elimination in patient-specific models of schizophrenia. http://biorxiv.org/lookup/doi/10.1101/231290 (2017) doi:10.1101/231290.

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