SfN 2007—MHC Class I and Complement: Holding Down Second Jobs in the Synapse
Editor's Note: With this meeting summary by guest writer Gwendolyn Wong, we kick off a series of summaries from the frontlines of basic neuroscience. Amidst 34,000 attendees (yes, you read right! 16,000+ posters, too!), Wong and our other correspondents found their way to some interesting sessions that reveal the diverse directions in basic neuroscience, some of which will likely influence schizophrenia sooner or later. Wong reports on a session entitled, "The New Neuroimmunology: Immune Proteins in Synapse Formation, Plasticity, and Repair," chaired by Lisa Boulanger of the University of California, San Diego.
18 November 2007. It may be a surprising idea, but it is becoming clearer from work done in several labs that complement factors and MHC Class I proteins are key regulators of synapse formation during fetal development, synapse plasticity, and synapse repair. This function occurs without apparent T cell involvement or any presentation of self or non-self peptides. It also now appears that these proteins may be relevant to neural disorders such as autism and schizophrenia, as discussed at a symposium held on 4 November 2007, at the Neurosciences 2007 meeting.
Carla Shatz of Harvard University first demonstrated that MHC Class I proteins were functionally required for development and plasticity of the CNS in 2000 (Huh et al., 2000). Today Shatz presented work from her laboratory—which primarily focuses on the visual cortex ocular dominance models of plasticity—showing that Class I proteins colocalize with PSD-95, considered by many a “master organizer of synapses” (see Goddard et al., 2007). Shatz demonstrated that Class I proteins are expressed at high levels in neurons of both somatosensory cortex as well as hippocampus. Using a double knockout mouse that lacks both β2-microglobulin (β2M) and the transporter associated with antigen processing 1 (TAP1), which dramatically reduces the surface expression of all MHC Class I proteins, Shatz and her colleagues showed that Arc (activity-regulated cytoskeletal-associated protein) induction in the visual cortex is abnormally widened after visual stimulation of the double knockout mice. These data suggest that MHC Class I proteins regulate the process of synaptic plasticity in the ocular dominance model used. Shatz proposed that the gene PirB (paired immunoglobulin-like receptor B) encodes the receptor for MHC Class I in neuronal synapses, which was shown previously to be expressed in neurons in the brain, and functions to limit experience-dependent plasticity in the visual cortex (Syken et al., 2006).
Staffan Cullheim of the Karolinska Institute in Stockholm, Sweden, used the same double β2M/TAP1 knockout mice to examine the role that Class I proteins play in the elimination of synapses following nerve injury (Thams et al., 2007; Cullheim and Thams, 2007). The data presented focused on the role of activated microglia and MHC Class I protein specificity in the synapse removal process after axotomy, and suggested that there may be a differential effect of these proteins in excitatory (NMDA) versus inhibitory (glycine or GABA) synapses, with more elimination of inhibitory synapses.
Ben Barres of Stanford University, Palo Alto, California, shifted the focus from MHC Class I proteins to the role of components of the complement cascade C1q and C3 to act as “punishment signals” and cause axon atrophy and withdrawal. Using a new imaging method called array tomography (Micheva and Smith, 2007), Barres showed that C1q colocalizes to developing CNS synapses using immunofluorescent staining of 70 nm sections of developing mouse brain. Barres further showed that in C1q or C3 knockout mice, synapse refinement that normally occurs in early postnatal development (P5 through P30) was defective, resulting in more synapses, not more neurons. Barres presented a model in which immature astrocytes clustering near the developing synapses release C1q and C3 into the synapse to prune and eliminate synapses. An important implication of Barres’s presentation is the tantalizing idea that inhibitors of the complement cascade may have the potential to block neurodegeneration.
The final talk of the symposium was by Lisa Boulanger. Boulanger has continued on with the work she had done as a postdoctoral fellow in Shatz’s laboratory, and has pursued studies of MHC Class I proteins in synaptic pruning and plasticity to explore the potential implications for both autism and schizophrenia. Boulanger is no stranger to the autism field, having published a thoughtful article on abnormal development of brain connectivity in autism in 2004 (Belmonte et al., 2004). In her talk, Boulanger examined the electrophysiological responses of β2M/TAP1 double knockout mice in paired pulse inhibition (an experimental model of sensory gating deficits in schizophrenia that is widely used, if not widely accepted), AMPA receptor fEPSP, and NMDA-induced chemical LTD, which is similar to low frequency stimulation induced LTD.
Surprisingly, the last test, which results in a stable LTD in wild-type mice, instead induced a robust LTP in the β2M/TAP1 double KO mice. Pursuing these studies further, Boulanger demonstrated that NMDA treatment caused a dramatic increase in surface AMPA receptor expression. Boulanger proposed that the increase in AMPA receptors was a result of increased internalization of AMPA, accompanied by a dramatic increase in recycling AMPA receptors back to the synaptic surface to cause a homeostatic shift of net increase.
Boulanger proposed that MHC proteins are tied to neural diseases, speculating that maternal immune challenge increases the risk of the unborn fetus to such diseases (see Patterson, 2007 and SRF related news story). In the model that Boulanger proposed, induction of a maternal immune response in mice increases maternal cytokines that are capable of entering the fetal blood circulation. These cytokines, if exposed to the developing nervous system of the fetus, may regulate MHC Class I levels in neurons. The question remains, Do changes in neuronal MHC Class I expression mediate changes in the development of the fetal brain?—Gwendolyn T Wong.
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Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of SchizophreniaComment by: Paul Patterson
Submitted 22 May 2006
Posted 22 May 2006
Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).
The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).
The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.
Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract
Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 Feb;26(2):204-15. Abstract
Brown AS. Prenatal infection as a risk factor for schizophrenia.
Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9.
Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001 Nov;58(11):1032-7. Abstract
Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33. Abstract
Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract
Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract
Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. Abstract
Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring.
J Neurosci. 2003 Jan 1;23(1):297-302.
Zuckerman L, Rehavi M, Nachman R, Weiner I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003 Oct;28(10):1778-89. Abstract
View all comments by Paul Patterson
Related News: Bad Timing: Prenatal Exposure to Maternal STDs Raises Risk of Schizophrenia
Comment by: Jürgen Zielasek
Submitted 3 June 2006
Posted 3 June 2006
Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.
Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.
However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.
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J Immunol. 2005 Dec 15;175(12):8096-104.
Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes.
J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11.
Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression.
Glia. 2006 Feb;53(3):248-56.
Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity.
J Immunother. 2005 May-Jun;28(3):220-8.
Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C).
J Immunol. 2005 Jan 15;174(2):992-1002.
Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells.
Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13.
Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract
View all comments by Jürgen Zielasek