1. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 0 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Neurochemical & Neuropathological Similarities in Autism & Schizophrenia Prince Nagra, Andrew Kuo, Alexandra Kourkounakis, Miles Luke October 14, 2014 Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 1 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Overview Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion

3. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 2 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia A neurodevelopmental disorder that hinders a child’s interactive and communicative capabilities. Categorized under the Autism Spectrum Disorder (ASD) ‘umbrella’ Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Symptoms: Varying degrees of severity Social impairments Repetitive actions Speech/Communication delays http://etec.ctlt.ubc.ca/510wiki/File:Umbie2.jpg Autism

4. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 3 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Autism Causes: Genetic Basis Candidate Genes Implicated Multigene Interaction Epigenetic 15q11-13 duplication 7q imprinting Environmental Factors Risk Factors: Sex of Child Family History Preterm infants Age of Parents Rett Syndrome and Fragile X Syndrome (Comorbidities)

5. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 4 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia A disabling mental disorder that distorts a person’s ability to behave, act, and discern the difference between reality and delusion. Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion PositiveNegative DelusionsEmotionless HallucinationsLack motivation Disorganized speech/thoughtsLoss of Interest Symptoms Schizophrenia

6. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 5 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Schizophrenia Causes: Genetic Basis multigene interactions Environmental Factors Substance Use toxic/induced psychosis Risk Factors: Family History Age of Father Prenatal Exposure to Toxins and Viruses Hypersensitive immune system

7. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 6 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion The fetal brain is extremely susceptible to developmental disruption caused during pregnancy Increased risk of autism and schizophrenia associated with prenatal maternal infection http://www.womancarehealth.com/363269/2012/02/06/prenatal-infection-prevention-month-gbs-facts.html Prenatal Infection

8. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 7 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion This suggests that commonalities between the immune responses to these pathogens may be involved in the etiology of autism and schizophrenia Berg, J. M., Tymoczko, J. L., and Stryer, L. (2012) Biochemistry, 7 th Ed. Prenatal Infection

9. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 8 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Pro-inflammatory cytokine IL-6 of particular interest –Abnormal behaviours and brain gene expression –Disruption of the GH/IGF-I axis https://www.bioscience.org/1996/v1/d/keller2/htmls/3.htm Prenatal Infection

10. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 9 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Lower Grey Matter Volumes Parahippocampal Gyrus Posterior Cingulate http://en.wikipedia.org/wiki/Parahippocampal_gyrus#mediaviewer/File:Gray727_parahippocampal_gyrus.png

11. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 10 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Lower Grey Matter Volumes Putamen Thalamus http://en.wikipedia.org/wiki/Putamen#mediaviewer/File:BrainCaudatePutamen.svg

12. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 11 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Insula Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Lower Grey Matter Volumes http://en.wikipedia.org/wiki/Insular_cortex#mediaviewer/File:Gray743.png

13. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 12 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia (Autism Spectrum Disorders) Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Cheung et al., 2010 Summary: Lower Grey Matter Volumes

14. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 13 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Basal Ganglia Loop Disruption Disruption within the basal ganglia loop systems is thought to explain impaired sensorimotor gating

15. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 14 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Neurotransmitters Serotonin –Regulate development of serotonergic neurons and target tissues –Lose serotonin terminals & neuronal development –Hyperserotonemia & animal research Dopamine –Cognition, motor function.... –Hyperactivity of dopamine transmission Dopaminergic neurons overactive –Repetitive, stereotyped behaviour, ↑activity, aggression

16. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 15 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion GABA –Inhibitory transmitter Glutamate –Excitatory transmitter Neurotransmitters

17. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 16 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Neurotransmitters exitotoxicity  aberrant neuronal development http://www.heartfixer.com/AMRI-Nutrigenomics.htm

18. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 17 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Oxytocin – Neurohypophysial hormone (hypothalamus)  PPG –Neuroanatomy of intimacy –Various behaviours Orgasm, social recognition, anxiety –Repetitive behaviour Hormones

19. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 18 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Common Medications Antipsychotics (improves social cognition) –Risperidone & Aripiprazole –Hyperactivity, aggression, stereotyped behaviour Neurohormonal neuromodulator oxytocin (improves social cognition, decreased repetitive behaviours, psychosis) http://commons.wikimedia.org/wiki/File:Risperidone.svg http://www.ramdevchem.com/Aripiprazole.asp Risperidone Aripiprazole

20. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 19 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Thank You For Your Time Future Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion

21. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 20 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Future Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Summary Slide Introduction Autism is a neurodevelopmental disorder that hinders a child’s interactive and communicative capabilities, classified as ASD. Schizophrenia is disabling mental disorder that distorts a person’s ability to behave, act, and discern the difference between reality and delusion. Has positive and negative symptoms. Prenatal Infection Linked to Schizophrenia and Autism Maternal prenatal infection increases risk of autism and schizophrenia in offspring Increased risk is not pathogen specific, so etiology is in common immune response Cytokines are small proteins involved in immune response that also affect neurodevelopment Neuropathological Similarities between Schizophrenia and Autism Lower grey matter volumes within limbic-striato-thalamic circuitry Specifically, the right parahippocampal gyrus, posterior cingulate, putamen, left thalamus and insula show lower grey matter volumes Disruption within the basal ganglia loop systems is also thought to explain impaired sensorimotor gating Neurochemical Similarities between Schizophrenia and Autism Neurotransmitters Serotonin, Dopamine, Glutamate increases Neurotransmitters GABA decreases Hormone Oxytocin decreases Common Medications include antipsychotics (dopamine blockers) and oxytocin

22. University of Toronto Leslie Dan Faculty of PharmacyPHM142 Metabolic Biochemistry & Immunology Intro 21 / 21 Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Specific Neurological Similarities in Autism & Schizophrenia Future Introduction Neuropathological Similarities Neurochemical Similarities Common Medications Conclusion Reference Slide 1.Berg, J. M., Tymoczko, J. L., and Stryer, L. (2012) Biochemistry, 7 th Ed. New York: W. H. Freeman and Company. 2.Cheung, C. et al. (2010). Autistic Disorders and Schizophrenia: Related or Remote? An Anatomical Likelihood Estimation. PLoS ONE 5, e12233. 3.Deveman, B. E. and Patterson, P. H. (2009). Cytokines and CNS development. Neuron. 64: pp. 61-78 4.Frago, L. M and Chowen, J. A. (2005). “Basic Physiology of the Growth Hormone/Insulin-Like Growth Factor (IGF)-Axis”. The Growth Hormone/Insulin-Like Growth Factor Axis During Development. Ed. Varela-Nieto, I. and. Chowen, J. A. New York: Springer. Advances in Medicine and Biology. 567: pp. 1- 26 5.Mescher, A. L. (2010). Junqueira’s Basic Histology: Text & Atlas, 12 th Ed. New York: McGraw-Hill Medical 6.Meyer, U., Feldon, J., and Dammann, O. (2011). Schizophrenia and autism: both shared and disorder- specific pathogensis via perinatal inflammation. Pediatr Res. 69(5): pp. 26R-33R. 7.Patterson, P. H. (2011). Maternal infection and immune involvement in autism. Trends Mol Med. 17(7): pp. 389-394. 8. Radeloff, D. et al. (2014). Structural Alterations of the Social Brain: A Comparison between Schizophrenia and Autism. PLoS ONE 9, e106539. 9.Ho, BC. et al. (2000). Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia. Am J Psychiatry 158(6): pp 986 10.Simic, M. et al. (2004). Autistic spectrum disorder associated with partial duplication of chromosome 15; three case reports. Eur Child Adolesc Psychiatry 6, 389-93