CINP summary – Examination of in vitro and in vivo microglial activity in neuropsychiatric disease

ian_everall_small_01From: Professor Ian Everall

Microglia are the brain’s immune cells that respond to any pathological event in the brain whether infectious or non-infectious (Nimmerjahn et al., 2005). Microglia respond to brain pathology by transforming from a resting to an activated state and by releasing various proinflammatory cytokines and free radicals, which, if prolonged, may cause secondary neuronal damage. Thus, persistent or uncontrolled activation of microglia is thought to contribute to secondary neuronal and axonal degeneration, decreased neurogenesis and synaptic dysfunction, and subsequently disease progression (Banati et al., 2002; Monji et al., 2009). As the microglial cell lineage is within the immune system, the cells emerge in the bone marrow and then migrate into the developing brain; very little attention has been given to their potential role in psychiatric disorders. However data is beginning to appear implicating microglia and ‘immune’ related pathway in psychiatric disorders.

Our group is now investigating microglia at both the microscopic level and in vivo using functional imaging.  Neuropathologically we have reported that the inflammatory protein calprotectin, which is expressed in microglia, is increased in the brain in schizophrenia (Foster et al., 2006) and more recently members of the tumour necrosis factor-alpha signaling pathway are abnormal in schizophrenia, bipolar disorder and major depression (Dean et al., 2013)Recently we demonstrated that the number or size of microglia are significantly increased in the frontal cortex in autism spectrum disorder (ASD) (Morgan et al., 2012; Morgan et al., 2010) and genes related to the metabotropic glutamate receptor five increased the risk of ASD (Skafidas et al., 2014).

Our in vivo imaging work has been investigating if microglia cell activation can be indexed by measuring the increase in the 18-kDa Translocator Protein (TSPO) using positron emission tomography (PET) and [11C]-(R)-PK11195 (Banati et al., 2002). Previous PET TSPO studies in schizophrenia suggest increased microglial activation in early, but not chronic, stages of the illness, although no studies have directly compared this. We are performing a cross-sectional and longitudinal imaging study in schizophrenia patients in the early stages of illness (mean 1.5 years), chronic illness (mean 15 years) and matched healthy controls. Compared to controls, our preliminary analysis demonstrates a significant difference in PK11195 uptake in the early illness, but not chronic, group, suggesting that microglia is altered at the early stages of schizophrenia. This is in line with our previous work demonstrating that progressive grey matter loss is most rapid at the earliest stages of the schizophrenia disorder (Pantelis et al., 2009). Given the link between microglial activation and neuronal damage, our future work will examine the association between microglia and markers of brain and clinical change. Specifically, we will examine the relationship between level of PET PK11195 and longitudinal change in grey matter and white matter connectivity. Correlations with peripheral immune mediators will also be assessed. Demonstrating such relationships will point to microglia/neuroinflammation as a mechanism underlying the progressive grey matter loss and dysconnectivity seen in the illness.   

 

Our program of neuropathological and imaging work will further inform the aetiopathological processes underlying progressive brain and clinical deterioration in psychiatric illness, and may provide a target for novel neuroprotective treatment strategies aimed at slowing or preventing illness progression. 

 

 

References

Banati RB. Glia (2002) 40: 206-17.

Dean, B., Gibbons, A.S., Tawadros, N., Brooks, L., Everall, I.P., Scarr, E., 2013. Different changes in cortical tumor necrosis factor-alpha-related pathways in schizophrenia and mood disorders. Mol Psychiatry 18, 767-773.

Foster, R., Kandanearatchi, A., Beasley, C., Williams, B., Khan, N., Fagerhol, M.K., Everall, I.P., 2006. Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? Eur J Neurosci 24, 3561-3566.

Monji A, et al. Psychiatry Clin Neurosci (2009) 63: 257-65.

Morgan, J.T., Chana, G., Abramson, I., Semendeferi, K., Courchesne, E., Everall, I.P., 2012. Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 1456, 72-81.

Morgan, J.T., Chana, G., Pardo, C.A., Achim, C., Semendeferi, K., Buckwalter, J., Courchesne, E., Everall, I.P., 2010. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68, 368-376.

Nimmerjahn A, et al. Science (2005) 308: 1314-8.

Pantelis C, Wood SJ. Ann Acad Med Singapore (2009) 38: 440-2.

Skafidas, E., Testa, R., Zantomio, D., Chana, G., Everall, I.P., Pantelis, C., 2014. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry 19, 504-510.

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