Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD.
Microglia and memory: modulation by early-life infection.
J Neurosci. 2011 Oct 26;31(43):15511-21.
PubMed.
Williamson and colleagues make an interesting and provocative link between immunity and memory. The central theme of their paper is that neonatal bacterial insult at the level of the periphery can have long-lasting negative effects on learning and memory later in adult life. Their work recalls that of Nobel laureate Mario Capecchi, who was the first to show a brain-immune connection with psychiatric disease. Specifically, his group demonstrated that deletion of the homeobox gene Hoxb8 in microglia profoundly disrupted neuronal physiology, resulting in disturbance of mouse circadian rhythms and development of the hair-pulling disease, trichotillomania (Greer and Capecchi, 2002; Chen et al., 2010). Capecchi and coworkers were able to ascribe their effects solely to microglia by performing a series of elegant rescue and microglia disease-transfer experiments that were groundbreaking (Chen et al., 2010).
Capecchi originally proposed both cell-surface and soluble factor mechanisms for microglia-neuron interaction. In the present paper, the authors have focused on the pro-inflammatory cytokine interleukin-1 β (IL-1β) as a central mediator of defective hippocampus-dependent memory. Specifically, the authors postulate a "two hit" model, where neonatal rats first encounter peripheral E. coli challenge and then have a second hit with the bacterial endotoxin, LPS. In this scenario, adult rats exhibit greatly elevated IL-1β levels restricted to the hippocampus, and perform poorly in a fear-conditioning behavioral assay. These effects paralleled microglial, but not astroglial activation, and occurred with neuronal inhibition as determined by expression of key microglial-neuron cell-surface interaction molecules (CD200-CD200R and CX3CL1-CX3CR1). Furthermore, the authors were able to demonstrate durable enhancement of IL-1β expression both in vivo and ex vivo in cultured microglia, and the anti-inflammatory agent minocycline was able to prevent exaggerated hippocampal IL-1β response and memory impairment in adult rats infected when they were neonates.
Like any thought-provoking work, the Williamson paper raises a number of questions. For example, it would be interesting to know whether IL-1β is upregulated in the hippocampus during the normal course of learning and memory, in the absence of bacterial challenge. Also, it has previously been shown that neuronal CD22 interacts with microglial CD45 to dampen down microglial activation (Mott et al., 2004). Perhaps the authors might also observe dysregulation of the CD22-CD45 axis in their two-hit model. Finally, while the authors’ conclusion that microglial IL-1β is the source of their behavioral phenotype may be valid, their data are mostly descriptive to this effect. It would be interesting to perform their two-hit model experiments in mice either sufficient for or deficient in IL-1β or caspase-1 (upstream of IL-1β) to definitively show this.
References:
Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR.
Hematopoietic origin of pathological grooming in Hoxb8 mutant mice.
Cell. 2010 May 28;141(5):775-85.
PubMed.
Greer JM, Capecchi MR.
Hoxb8 is required for normal grooming behavior in mice.
Neuron. 2002 Jan 3;33(1):23-34.
PubMed.
Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J.
Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production.
Glia. 2004 May;46(4):369-79.
PubMed.
Comments
University of Southern California
Williamson and colleagues make an interesting and provocative link between immunity and memory. The central theme of their paper is that neonatal bacterial insult at the level of the periphery can have long-lasting negative effects on learning and memory later in adult life. Their work recalls that of Nobel laureate Mario Capecchi, who was the first to show a brain-immune connection with psychiatric disease. Specifically, his group demonstrated that deletion of the homeobox gene Hoxb8 in microglia profoundly disrupted neuronal physiology, resulting in disturbance of mouse circadian rhythms and development of the hair-pulling disease, trichotillomania (Greer and Capecchi, 2002; Chen et al., 2010). Capecchi and coworkers were able to ascribe their effects solely to microglia by performing a series of elegant rescue and microglia disease-transfer experiments that were groundbreaking (Chen et al., 2010).
Capecchi originally proposed both cell-surface and soluble factor mechanisms for microglia-neuron interaction. In the present paper, the authors have focused on the pro-inflammatory cytokine interleukin-1 β (IL-1β) as a central mediator of defective hippocampus-dependent memory. Specifically, the authors postulate a "two hit" model, where neonatal rats first encounter peripheral E. coli challenge and then have a second hit with the bacterial endotoxin, LPS. In this scenario, adult rats exhibit greatly elevated IL-1β levels restricted to the hippocampus, and perform poorly in a fear-conditioning behavioral assay. These effects paralleled microglial, but not astroglial activation, and occurred with neuronal inhibition as determined by expression of key microglial-neuron cell-surface interaction molecules (CD200-CD200R and CX3CL1-CX3CR1). Furthermore, the authors were able to demonstrate durable enhancement of IL-1β expression both in vivo and ex vivo in cultured microglia, and the anti-inflammatory agent minocycline was able to prevent exaggerated hippocampal IL-1β response and memory impairment in adult rats infected when they were neonates.
Like any thought-provoking work, the Williamson paper raises a number of questions. For example, it would be interesting to know whether IL-1β is upregulated in the hippocampus during the normal course of learning and memory, in the absence of bacterial challenge. Also, it has previously been shown that neuronal CD22 interacts with microglial CD45 to dampen down microglial activation (Mott et al., 2004). Perhaps the authors might also observe dysregulation of the CD22-CD45 axis in their two-hit model. Finally, while the authors’ conclusion that microglial IL-1β is the source of their behavioral phenotype may be valid, their data are mostly descriptive to this effect. It would be interesting to perform their two-hit model experiments in mice either sufficient for or deficient in IL-1β or caspase-1 (upstream of IL-1β) to definitively show this.
References:
Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010 May 28;141(5):775-85. PubMed.
Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron. 2002 Jan 3;33(1):23-34. PubMed.
Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J. Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia. 2004 May;46(4):369-79. PubMed.
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