Synaptic Pruning and Schizophrenia – Role of Microglia and Future Directions
Synaptic pruning is an important developmental process that refines and optimises neuronal transmission.
In the healthy developing brain, this process is performed by the brain’s resident population of microglial cells. Microglia are commonly referred to as the immune cells of the CNS; however, they are dynamic and responsive cells that contribute to many physiological functions in the brain [Casano and Peri, 2015]:
- Microglia are primary innate immune cells that are phenotypically different and developmentally distinct from other macrophage populations in the periphery. Thus, they can be considered the ‘professional phagocytes’ in the central nervous system (CNS).
- Microglia also play a functional role in brain development, including the secretion of diffusible factors that stimulate synaptic formation, as well as phagocytosing of synaptic elements, axons, and dying cells.
- For example, in Alzheimer’s disease, microglia play a critical role in the uptake and proteolytic clearance of both soluble and fibrillary forms of β-amyloid.
- In addition to removing dying neurons, microglia might also actively promote neuronal cell death through a process known as “primary phagocytosis” or “phagoptosis.
- While microglia promote neuroprotection, TLR-induced activation of microglia and the release of pro-inflammatory molecules are responsible for neurotoxic processes in the course of various CNS diseases. Thus, the functional outcome of TLR-induced activation of microglia in the CNS depends on a subtle balance between protective and harmful effects. [Lehnardt, 2010]
MICROGLIA AND SYNAPTIC PRUNING
One of the specialised roles of microglia is to prune developing synapses, thus regulating synaptic plasticity and function. [Holtmatt and Svoboda, 2009]
From the earliest embryonic stage, the brain develops more neurons and synapses than are functionally needed:
- Synaptic density in the infant human brain reaches a maximum number at the age of 2 to 4 years old and is approximately double what is found in adults. [Huttenlocher,1979], [Huttenlocher and Dabholkar, 1997]
- Over time, developing synapses are either selectively stabilised by neuronal activity or are eliminated by pruning. [Hua and Smith, 2004]
- The complement cascade plays an integral role in the ‘tagging’ of unnecessary synapses, which are subsequently recognised and phagocytosed by nearby microglia.
- Optimised synaptic density in cerebral cortical tissue is necessary to provide the necessary synapse number and synaptic density for cognition.
The complement cascade has traditionally been viewed as an integral part of the immune system whereby it augments an antibodies’ antibacterial activity. However, the complement system has also been documented to be associated with the remodelling of neuronal connections and the process of synaptic pruning. [Stevens et al., 2007]
During microglial-mediated brain development, the C1q ligand is expressed on the surface of synapses and functions as a signal to microglia for destruction. C1q-mediated synaptic pruning has also been recently described in early-stage synapse loss in Alzheimer’s disease and frontotemporal dementia. [Hong S et al., 2016], [Lui et al., 2016]
A previous study showed a strong association between the DNA region on chromosome 6, which codes for complement component 4 (C4) and schizophrenia. [Sekar et al., 2016]
C4 plays a key role in the pruning of synapses during a key time in the development of the brain. Researchers found that the genetic variation of C4 strongly correlated with the presence of schizophrenia. [Read the summary here]
SYNAPTIC DENSITY AND SCHIZOPHRENIA
Since Feinberg first reported in 1982 that schizophrenia might be a result of “…a defect of synaptic elimination programmed to occur during adolescence” [Feinberg, 1982-1983], human clinical, epidemiological, neuroimaging, and post-mortem data have provided evidence that schizophrenia is a neurodevelopmental disorder caused by dysfunctional synaptic elimination [Faludi and Mirnics, 2011]:
- Schizophrenia typically develops during adolescence, and early adulthood and post-mortem studies show a loss of cortical volume in the brains of patients with schizophrenia. [Hof and Schmitz, 2009]
- Overall there is an enlargement of the ventricles, a 3% reduction in brain volume and grey matter reductions of between 6 to 10% in specific regions such as in the hippocampus and the frontal cortex. [Turetsky et al., 1995], [Fornito et al., 2009] , [Heckers and Konradi, 2010]
- In post-mortem cortical samples from schizophrenia patients, the synaptic protein marker, synaptophysin, is significantly decreased in the hippocampus, cingulate cortex, and frontal cortex compared to healthy human samples. [Osimo et al.,2018]
However, despite these observations, there is no clear evidence of neuronal loss or degenerative changes in patients with schizophrenia. [Thune et al., 2001]
Instead, it is suggested that the reduction in synaptic density results in lower grey matter volumes. [Lewis and Levitt, 2002]
Although, neural development, disruptions to energy homeostasis, genetic predisposition, immunological processes, and environmental factors are also likely to contribute and uniquely influence synaptic connectivity for each patient. Therefore, when taken together, this could explain the symptom heterogeneity of schizophrenia when considering the neurodevelopmental hypothesis of schizophrenia.
RECENT NOVEL RESEARCH
Sellgren and colleagues recently published data from an in vitro model that uses patient-derived human cells and induced microglia-like cells to observe synaptic pruning. [Sellgren et al., 2019]
In this groundbreaking study:
- Microglia from patients with schizophrenia were more active.
- Several genes associated with the complement system had an increased expression level linked with increased microglial uptake.
- Interestingly, minocycline prevented synaptic engulfment in their in vitro model.
- Therefore, excessive synaptic pruning is a potential therapeutic target for individuals classified as having a high risk of developing schizophrenia.
Minocycline is a semi-synthetic second-generation tetracycline that is effective against gram-positive and gram-negative infections. However, it is also often prescribed for inflammatory disorders such as rheumatoid arthritis due to its ability to suppress inflammatory mediators (e.g. nitric oxide). Minocycline has also previously been suggested to be neuroprotective by reducing macrophage/microglial activation. [Stirling et al., 2005]
Read about Minocycline in Depression.
- Minocycline has been trialled in several neurological disorders such as multiple sclerosis, stroke, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. [Kim and Suh, 2009]
- Mixed results in trials of neurodegenerative diseases with no effect in amyotrophic lateral sclerosis were reported. [Gordon et al., 2007]
- A recent RCT showed that minocycline did not improve total PANSS or PANSS subscales compared to placebo in 200 patients with schizophrenia or schizoaffective disorder. [Weiser et al., 2018]
- However, there have been positive results in a phase 2 trial of 27 patients with acute traumatic spinal cord injury. [Casha et al., 2012]
The aetiological involvement of microglia and the immune system in human neurological and psychiatric disorders has garnered significant interest recently.
Although more work is needed, microglia-mediated synaptic elimination may become an important therapeutic target in the prevention of disorders like schizophrenia.
Learn more about neuroinflammation.