SnapShot: Microglia in Disease

1294 Cell 165, May 19, 2016 © 2016 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2016.05.036

See online version for legend and references.

Microglia

Abnormal connectivity

Decreased C3 expression Retention of immature synapses

AUTISM SPECTRUM DISORDERS

Microglia

NEURON

High risk

Schizophrenia

Increased microglial activity and pruning

Healthy

SCHIZOPHRENIA

Pre-synaptic

Synaptic terminal

C3 CR3

Birth

Adult

AD Aged

Increased C3 with age Microglia drawn to plaque deposits

Amyloid plaque

ALZHEIMER’S DISEASE

Adolescence

SCHIZO

ASD

Synaptic density across lifetime

Microglia

DENDRITE

Synaptic pruning

Simon Beggs1,2 and Michael W. Salter1 1 Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto ON M5G 1X8, Canada 2 Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK

SnapShot: Microglia in Disease

Synaptic density

P2X4

P2X4

BDNF

Spinal inhibition

Pain signaling to brain

P2X4R+ microglia in spinal dorsal horn

CSF1R

CSF1

PA I N

SnapShot: Microglia in Disease Simon Beggs1,2 and Michael W. Salter1 1 Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto ON M5G 1X8, Canada 2 Developmental Neurosciences Programme, UCL Institute of Child Health, London WC1N 1EH, UK The development and maintenance of the central nervous system is dependent upon regulated, homeostatic actions of microglia, which sculpt and refine neuronal circuitry. By contrast, dysregulation of microglia contributes to the pathology of neurodevelopmental disorders such as autism spectrum disorders; neurodegenerative disorders such as Alzheimer’s disease; and schizophrenia and chronic neuropathic pain. Introduction Microglia are yolk-sac-derived, monocyte-lineage cells, which, in addition to performing an immune role in the central nervous system (CNS), are necessary for normal CNS development and subsequent maintenance (Salter and Beggs, 2014). Microglia occupy non-overlapping microdomains forming a grid-like 3-dimensional array, making them ideally distributed to monitor and influence neuronal function. In their physiological, “surveillance” state, microglia have numerous ramified processes that constantly extend and retract to continuously sample their microenvironment. This surveillance clearly aids microglia in fulfilling their immune function in the CNS, monitoring continuously for damage, injury, or disease, but it also facilitates a further function of microglia—synaptic pruning (Schafer et al., 2012). Microglia regulate major aspects of synapse development, plasticity, and function, sculpting and refining synaptic circuitry by removing excess and unwanted synapses, vital for normal CNS health. By extension, disease states might not need to involve a pathological gain in microglial function but simply a disruption of their physiological functioning in synaptic regulation. Thus, brain disorders long considered to be based on defective neuronal functioning may be more accurately described as disorders of microglia-neuron interaction. Complement in Synaptic Pruning The complement cascade, normally associated with removal of pathogens and cellular debris, is also crucial to microglial-mediated synaptic pruning and refinement of neuronal connectivity in the normal brain (Stevens et al., 2007). Evidence points to convergence on C3 and its microglial receptor C3R. The initiator of the complement cascade is C1q, which induces C3 secretion via C4. The presence of C3 on unwanted synapses “tags” them for recognition by microglia to be eliminated. Schizophrenia Genome-wide association studies (GWAS) have identified strong risk association for schizophrenia in the major histocompatibility complex (MHC) locus, a large region on chromosome 6. Within the MHC, highest association occurs with diverse alleles of C4 genes, which encode the complement C4 proteins (Sekar et al., 2016). Schizophrenia risk is increased with higher expression of the C4A isotype. In the mouse, only one form of C4 exists, and its expression is highest during periods of normal synaptic pruning. Knocking out C4 in mice decreases synaptic pruning, consistent with increased human C4A expression associated with increased synaptic pruning. Synaptic refinement occurs throughout the lifespan with mature neural circuitry being refined through the peak of synaptic elimination occurring in the adolescent and early adult brain, corresponding to the peak risk for schizophrenia onset. Supporting a role for microglia is evidence that binding of (11C)PBR28, a microglia-specific ligand, is far more widespread in schizophrenia patients compared with controls (Bloomfield et al., 2016). Intriguingly, (11C)PBR28 binding is also elevated in patients deemed to be at-risk for schizophrenia, suggesting that microglia may contribute to disease onset. Diverse pathways might interact with the complement system causing excessive microglia-mediated synapse elimination during adolescence and early adulthood, accounting for loss of gray matter and reduced synaptic density seen in schizophrenia patients. Alzheimer’s Disease Microglia-mediated neuroinflammation is a hallmark of late-stage Alzheimer’s disease (AD), and microglial genes have been identified in GWAS of this disease. It is hypothesized that phagocytic microglia are attracted to plaques in an attempt to clear them and that the inability to clear plaques coupled with an increasingly toxic sustained neuroinflammatory response accelerates synaptic loss and cognitive decline. However, synaptic dysfunction and loss occur long before signs of neuropathology and cognitive impairment. Recently, C1q has been shown to be necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses (Hong et al., 2016), suggesting that microglia can act as early mediators of synapse loss and dysfunction before plaque formation. While the pathology of AD is defined by the presence of plaques, tau tangles, and ongoing neuronal loss, it is synaptic loss that has the strongest correlation with cognitive decline. In the 5xfAD mouse model of AD, plaques form, and there is synaptic and neuronal loss with corresponding deficits in cognition. Eliminating ~80% of microglia in these mice, by blocking the CSF1 receptor, has no effect on plaque or tau deposits, but CSF1R inhibition reverses dendritic spine loss, prevents neuronal loss, and reverses deficits in contextual memory, despite the disease being at an advanced stage (Spangenberg et al., 2016). Is it therefore the case that the action of microglia in AD contributes to the cognitive symptoms but not the progression of Aβ deposition? Autism Syndrome Disorders A deficit in microglia/complement-mediated synaptic pruning may be fundamental to the cognitive effects associated with autism syndrome disorders (ASDs) (Voineagu et al., 2011). Decreased C4 leading to reduced synaptic pruning in early life, mediated through reduced C3 synaptic tagging, is implicated in ASD-like behaviors (Estes and McAllister, 2015). Furthermore, mice deficient in the CX3CR1, a chemokine receptor expressed in the brain exclusively by microglia, have increased densities of immature synapses in the cortex and deficits in functional connectivity. Pain Peripheral neuropathic pain is a debilitating condition arising from damage to peripheral sensory nerves. Microglia in the spinal cord respond to such injury by adopting a reactive state characterized by upregulation of the purinergic P2X4 receptor (Mapplebeck et al., 2016). Activating P2X4Rs initiates a signaling pathway ultimately leading to neuronal disinhibition in spinal nociceptive circuitry, resulting in pain hypersensitivity. Surprisingly, the involvement of microglia in neuropathic pain hypersensitivity is a sexually dimorphic response, only occurring in males (Mapplebeck et al., 2016). Conclusion Dysregulation of normal microglial functions such as synaptic pruning and regulation is increasingly implicated in diseases associated with cognitive deficits. Targeting of these dysregulated microglial functions represents a therapeutic opportunity for treating these disorders. Given the sex bias of diseases with a neuroimmune pathology, including AD and ASD, it remains to be seen if microglial function in these disorders exhibits mechanistic sex differences, as seen in neuropathic pain. REFERENCES Bloomfield, P.S., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D.R., Bloomfield, M.A.P., Bonoldi, I., Kalk, N., Turkheimer, F., et al. (2016). Am. J. Psychiatry 173, 44–52. Estes, M.L., and McAllister, A.K. (2015). Nat. Rev. Neurosci. 16, 469–486. Hong, S., Beja-Glasser, V.F., Nfonoyim, B.M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K.M., Shi, Q., Rosenthal, A., Barres, B.A., et al. (2016). Science 352, 712–716. Mapplebeck, J.C.S., Beggs, S., and Salter, M.W. (2016). Pain 157 (Suppl 1), S2–S6. Salter, M.W., and Beggs, S. (2014). Cell 158, 15–24. Schafer, D.P., Lehrman, E.K., Kautzman, A.G., Koyama, R., Mardinly, A.R., Yamasaki, R., Ransohoff, R.M., Greenberg, M.E., Barres, B.A., and Stevens, B. (2012). Neuron 74, 691–705. Sekar, A., Bialas, A.R., de Rivera, H., Davis, A., Hammond, T.R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., et al.; Schizophrenia Working Group of the Psychiatric Genomics Consortium (2016). Nature 530, 177–183. Spangenberg, E.E., Lee, R.J., Najafi, A.R., Rice, R.A., Elmore, M.R.P., Blurton-Jones, M., West, B.L., and Green, K.N. (2016). Brain 139, 1265–1281. Stevens, B., Allen, N.J., Vazquez, L.E., Howell, G.R., Christopherson, K.S., Nouri, N., Micheva, K.D., Mehalow, A.K., Huberman, A.D., Stafford, B., et al. (2007). Cell 131, 1164–1178. Voineagu, I., Wang, X., Johnston, P., Lowe, J.K., Tian, Y., Horvath, S., Mill, J., Cantor, R.M., Blencowe, B.J., and Geschwind, D.H. (2011). Nature 474, 380–384.

1294.e1 Cell 165, May 19, 2016 © 2016 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cell.2016.05.036