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Progress in Understanding the Neurobiology of Schizophrenia Daphne Holt, MD, PhD Director of Research, Schizophrenia Clinical and Research Program Department.

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Presentation on theme: "Progress in Understanding the Neurobiology of Schizophrenia Daphne Holt, MD, PhD Director of Research, Schizophrenia Clinical and Research Program Department."— Presentation transcript:

1 Progress in Understanding the Neurobiology of Schizophrenia Daphne Holt, MD, PhD Director of Research, Schizophrenia Clinical and Research Program Department of Psychiatry, Massachusetts General Hospital Schizophrenia Education Day November 10, 2012

2 Overview What causes schizophrenia? –Genes AND environment What changes occur in the brain in schizophrenia? –Changes in neurotransmitters: dopamine –Changes in brain structure and function –Effects of risk genes on the brain Summary & the future

3 genetic vulnerability, present from birth changes in brain structure/function symptoms and impaired functioning stressful prenatal or later-in-life events, developmental stages The overall picture

4 Schizophrenia is caused partly by genes that increase vulnerability to developing the disorder Family studies: –first degree relatives have a 10X higher risk than the average risk level of 1/100 –an identical twin has a > 50X higher risk Adoption studies: –Children of mothers with schizophrenia who are adopted into families without schizophrenia develop schizophrenia at a higher rate than their biologically unrelated adoptive siblings (Kety, 1976, 1978)

5 WHAT WE HAVE RECENTLY LEARNED: there is no one schizophrenia gene Many common genetic variants (versions of genes) increase risk for schizophrenia very slightly Over 20 of these commonly found risk variants have been identified during the past 5 years There are also a few rare genetic variants that increase risk for schizophrenia to a larger extent, called Copy Number Variants (CNVs) These common and rare risk variants likely interact with each other, and with environmental risk factors, to increase a person’s vulnerability for developing schizophrenia

6 GenesEnvironment Multiple common genetic variants with small effects And rare genetic variants with larger effects EARLY: elevated paternal age, obstetric complications, viral infections or malnutrition during the mother’s pregnancy LATER: cannabis use, urban environment, being a minority or immigrant Schizophrenia

7 Some of these risk genes probably influence early brain development Fischl, Yu, Busa, Pienaar and Grant

8 Some of these risk genes may affect the brain indirectly For example, some of the genetic variants most consistently found to increase risk for schizophrenia are important for the normal, healthy functioning of the immune system One way these genes might increase risk for schizophrenia: –making it harder for a fetus to get rid of an infection, leading to harmful effects of that infection on the developing brain

9 WHAT WE HAVE RECENTLY LEARNED: many of the genes that increase risk for schizophrenia, also increase risk for other brain disorders Including Bipolar Disorder, Epilepsy, Attention Deficit Disorder and Autism There are no “schizophrenia genes” Rather than causing a specific disorder, genes may lead to changes in particular brain functions, giving rise to specific symptoms: –delusions, hallucinations, mood dysregulation, attentional problems, problems with social interactions

10 WHAT WE HAVE RECENTLY LEARNED: genetic changes that increase risk for schizophrenia are not necessarily inherited over generations For example, in older fathers, there are more mutations in the DNA carried by sperm cells (compared to younger fathers) These new, non-inherited mutations by chance may occur in a gene that is important for brain development or function and increase risk for schizophrenia

11 genetic vulnerability, present from birth changes in brain structure/function symptoms and impaired functioning stressful prenatal or later-in-life events, developmental stages The overall picture

12 Laruelle et al, Biol Psych 1999 There is too much dopamine released by the brain in people with schizophrenia during psychotic episodes

13 Reith et al, 1994Pearlson et al, 1995 This abnormality is not specific to schizophrenia but to psychosis  seen in other disorders

14 Hirvonen et al, Am J Psych 2005 Caudate nucleus D2 dopamine receptor binding: MZ unaffected co-twins > DZ unaffected and healthy co-twins Caudate D2 receptor binding WHAT WE HAVE RECENTLY LEARNED: abnormalities in dopamine are present in those at risk for developing psychosis

15 Howes et al, Am J Psych 2011 Dopamine synthesis in the brain may be greater in young people who later develop a psychotic disorder, compared to those who do not

16 Kuperberg et al, Arch Gen Psych 2003 Some brain regions are smaller than average in some people with schizophrenia

17 Nakamura et al, Biol Psych 2007 Kasai et al, Am J Psych 2003 WHAT WE HAVE RECENTLY LEARNED: some of these changes in the brain may occur during the early years of the illness

18 Specific types of therapy may reverse or prevent these changes Eack et al, Arch Gen Psych 2010

19 And lead to improvements in social and cognitive functioning

20 Meyer-Lindenberg et al, Nat Neurosci 2002 Cognitive function (and the involved brain regions) is affected in schizophrenia  attention and memory capacities can be reduced

21 D. SCZ * Brain activity to safety signals WHAT WE HAVE RECENTLY LEARNED: The regions of the brain important for emotional function are also affected in schizophrenia ControlsPeople with schizophrenia * * Brain activity to threat signals Some people with schizophrenia do not respond to signals in the environment indicating that a situation is safe Holt et al, Arch Gen Psych 2012

22 Poor safety signaling in schizophrenia: reduced activity of the ventromedial prefrontal cortex Brain Activity during Safety Signaling: CON vs. People with delusions (D) D > CONCON > D p <.05 B.A. * * CONNDD ** x = 6 *p <.05 ** p <.005 Abnormalities in cognitive and/or emotional function may give rise to certain symptoms of schizophrenia, such as delusions Holt et al, Arch Gen Psych, 2012 D = people with schizophrenia with delusions ND = people with schizophrenia without delusions CON = controls

23 We now have quantitative methods to measure the strength of the connections of the brain

24 One example: there is reduced communication between two cortical areas (within the cingulate gyrus) in schizophrenia Correlation (r) Controls * Schizophrenia * Holt et al, Biol Psych 2011, WHAT WE HAVE RECENTLY LEARNED: The connections and communication among different brain regions are affected in schizophrenia

25 Egan et al, PNAS 2001 For example: the number of a particular variant of a gene you have (Met allele load of the catechol-O-methyltransferase (COMT) gene) predicts the function of the prefrontal cortex and memory ability WHAT WE HAVE RECENTLY LEARNED: Genes influence brain structure and function in a way we can reliably measure

26 Ehrlich et al, Neuroimage 2010 ? These same genetic variants can also influence the basic structure of the brain For example: COMT met allele load predicts amygdala and hippocampal sizes

27 = Left DLPFC ROI C/C (n=41) minus T carrier (n=38) SCHIZOPHRENIA = Left DLPFC ROI C/C (n=35) minus T carrier (n=40) CONTROLS Some genetic variants exert a larger influence on brain structure or function in people with schizophrenia than in people without schizophrenia Example: MTHFR C 677 T effects on prefrontal activity during working memory Roffman et al, PNAS 2009

28 Summary & the future Take home points: –Genetic AND environmental factors play a role in causing schizophrenia –Environmental factors = modifiable risk factors –There are many genes that slightly increase risk for schizophrenia and other disorders  there is no “schizophrenia gene” –There are many subtle changes in brain structure and function that occur in schizophrenia, which are related to changes in cognitive and emotional function and symptoms –Some of these changes may be partially reversible or preventable with new treatments currently in development

29 Modified from: Feuk et al. Nature Reviews Genetics 2006 Genomic DNA Label reference and test DNA and hybridize Microarrays Array spotted with computationally designed oligonucleotide probes PCR amplification (<1.2 kb) Adaptor ligation Bglll digested The Future: High-density microarrays allow rapid, genome-wide assessment

30 The Future: Decreasing cost, increasing throughput of genotyping over time Taqman (1) SBE-FP (1) Affymetrix (500K) Sequenom Mass Spec (5) Illumina (1536)

31 The Future: higher resolution imaging of brain structure (sub-millimeter) 1mm

32 Thank you for your attention! Questions?


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