MENTAL DISORDERS RESULTING FROM PRENATAL INFECTIONS PRESENTER – ROLANO Q. NUNEZ PROJECT SUPERVISOR – PROFESSOR TREVOR STONE

PRESENTATION OVERVIEW History & Epidemiology/Serology Mental Disorders - Schizophrenia - Autism Prenatal infections Animal Models - Rodents Questions?

MAIN QUESTION TO BE ANSWERED DOES INFECTION DURING PREGNANCY (PRENATAL INFECTIONS) CAUSE BRAIN DISORDERS IN THE OFFSPRING?

HISTORICAL SPECULATIONS Emil Kraepelin (15 February 1856 – 7 October 1926) “infections in the years of development might have a causal significance” for dementia praecox.

HISTORICAL SPECULATIONS Karl Menninger (July 22, 1893 – July 18, 1990) “After 1919 influenza pandemic, Karl Menninger speculated that infection may be causally related to schizophrenia. He then retracted his statement In 1928”

PIONEERING RESEARCH THAT CONFIRMS SPECULATIONS

EPIDEMIOLOGY & IT’S LIMITATION

AUTISM - RUBELLA EPIDEMICS 1960S STRONG EFFECTS IN POSTNATAL OFFSPRING Cytomegalovirus (CMV) Toxoplasmosis (parasitic disease) - Protozoan ‘Toxoplasma Gondii’ - Infection via faecal (poop) contamination - MEOW! Varicella virus (herpes virus) - Common cause for shingles & chicken pox Measles (paramyxovirus) - Infection of respiratory system Mumps Herpes Simplex 2 (HSV-2)

SCHIZOPHRENIA Maternal influenza Maternal toxoplasmosis Rubella (Rubella virus) / German Measles - Contact during 20 weeks of gestation (1 st trimester) - Congenital rubella syndrome (CRS) Bacterial infections - Diphtheria - Pneumonia Herpes Simplex 2 (HSV-2) Patent ductus arteriousus (PDA)  Congenital heart disorder  Ductus arteriousus fails to close after birth  May lead to congestive heart failure

IMMUNOGENS USED TO INDUCE MATERNAL IMMUNE ACTIVATION IN ANIMALS LPS (lipopolysaccharide) - Cell wall component of Gram –ve bacteria - Mimics bacterial infections [poly (I:C)] (polyinosinic:polycytidylic acid) - Synthetic double stranded RNA (dsRNA) - Mimics viral infections Maternal influenza - Live virus - Intranasal administration

CYTOKINE HYPOTHESIS Protein mediators (kinase signaling) -NF-kB -MAPK -JAK/STAT Immunological defense -Infections -Immune activation -Stress Specific cytokines produced (LPS) – TLR 4 -TNF α, IL1 β, IL6 [poly (I:C)] – TLR 3 -TNF α, IL1 β, IL6, IL10 (influenza) -Similar protein mediators of cytokines released Cytokine receptors are expressed both in developing & mature neurons and can cause morphological and functional changes in those cells. (Gilmore et al., 2004 & Bauer et al., 2007) RADIOLABELLED IMMUNOGEN

IN-VIVO RODENT MODELS OF PRENATAL IMMUNE ACTIVATION RATMOUSE ANIMAL MODELS

ABNORMALITIES OBSERVED IN MENTAL DISORDERS BEHAVIOURAL MORPHOLOGICAL STRUCTURAL MOLECULAR NEUROCHEMISTRY

ABNORMALITIES OBSERVED IN OFFSPRING RODENT MODELS

TABLE 1 : ACUTE CHANGES IN FETAL COMPARTMENT

TABLE 2 : BEHAVIOURAL ABNORMALITIES

PREPULSE INHIBITION (PPI)?

TABLE 3 : MORPHOLOGICAL CHANGES

TABLE 4 : CHANGES IN NEUROTRANSMITTER SYSTEM & CNS ELECTROPHYSIOLOGY

TABLE 5 : MOLECULAR CHANGES

OTHER ANIMAL MODELS OF PRENATAL INFECTION

BUT ITS NOT OVER YET A question for thought: “How is the disorders differentiated to become Schizophrenia or Autism specifically in adolescence following adulthood?

LAYMANS TERMS: WHY IF YOU TREAT PREGNANT DAMS WITH POLY (I:C) OR LPS IT GIVES RISE TO SCHIZOPHRENIA OR AUTISM? Timing? Dose? Strain of pathogen? Severity of infection? MECHANISMS STILL UNCLEAR

CONCLUSION

SUMMARY History & Epidemiology/Serology Mental Disorders - Schizophrenia - Autism Prenatal infections Animal Models