The microglial basis of major depressive disorder

Mark Mizee, postdoc

Major depressive disorder (MDD) is the most prevalent psychiatric disorder, affecting over 350 million worldwide, and is the leading cause of disability in the western world. Novel therapies are urgently needed, and require a better understanding of the underlying cellular mechanisms of MDD.

Changes in microglia function have been linked to major depression as well as other major psychiatric disorders. Classically considered to be just immune cells of the brain, today we know that microglia perform a wide range of functions from brain development to regulation of mood. However, when microglia overreact or fail to respond sufficiently to changes in their environment, this negatively affects the homeostasis of surrounding cells and therefore hampers normal brain function in those regions. No clear picture exists regarding human microglia-specific pathways underlying depressive symptoms. The psychiatry program of the Netherlands Brain Bank (NBB-Psy) is crucial in providing well-characterized brain tissue and curating clinical donor information needed for this type of research.

We study the microglial role in MDD using two approaches:

1. Freshly dissected post-mortem brain tissue from control and MDD donors is used to purify intact microglia using our microglia isolation protocol1,2. Microglia transcriptomic profiles are generated by qPCR and RNA sequencing (in progress) and show that while white matter microglia from control and MDD do not differ, whereas occipital cortex microglia show increased expression of genes associated with microglial homeostasis.
2. A limitation of using fresh tissue is the unavailability of clinical and neuropathological information. By using our newly developed method to purify cell specific nuclei from frozen brain samples, we can generate microglial transcriptomic data from matched and characterized brain donors, as well as select specified brain regions as a tissue source. This allows us to validate the microglial changes found in approach 1 using different brain regions known to be affected in MDD symptomatology. We will also use the same tissue source to validate promising mechanisms using immunohistochemistry.

Figure 1. Purification of microglial nuclei, but also other celltypes, is possible from frozen human brain samples and will be used for transcriptomic profiling.

Combined, we will unravel novel biological mechanisms underlying depressive symptoms. Subsequently, we will use operational primary microglial culture models3 to better understand the cellular mechanisms at play, for instance in the degradation of synaptic structures by microglia.

• Mizee, M. R. et al. Isolation of primary microglia from the human post-mortem brain: effects of ante- and post-mortem variables. Acta Neuropathol. Commun. 5, 16 (2017).
• Mizee, M. R., Poel, M. van der & Huitinga, I. Purification of cells from fresh human brain tissue: primary human glial cells. in Handbook of clinical neurology 150, 273–283 (2018).
• Hendrickx, D. A. E., Schuurman, K. G., van Draanen, M., Hamann, J. & Huitinga, I. Enhanced uptake of multiple sclerosis-derived myelin by THP-1 macrophages and primary human microglia. J. Neuroinflammation 11, 64 (2014).