Progress in Understanding the Neurobiology of Schizophrenia

Daphne Holt, MD, PhDDirector of Research, Schizophrenia Clinical and Research Program

Department of Psychiatry, Massachusetts General Hospital

Schizophrenia Education DayNovember 10, 2012

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

genetic vulnerability, present from birth

changes in brain structure/function

symptomsand impaired functioning

stressful prenatal or later-in-life events, developmental stages

The overall picture

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)

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

Genes Environment

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

Some of these risk genes probably influence

early brain development

Fischl, Yu, Busa, Pienaar and Grant

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

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

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

genetic vulnerability, present from birth

changes in brain structure/function

symptomsand impaired functioning

stressful prenatal or later-in-life events, developmental stages

The overall picture

Laruelle et al, Biol Psych 1999

There is too much dopamine released by the brain in people with schizophrenia during psychotic episodes

Reith et al, 1994 Pearlson et al, 1995

This abnormality is not specific to schizophrenia but to psychosis seen in other disorders

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

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

0.0010.1 0.050.001

Kuperberg et al, Arch Gen Psych 2003

Some brain regions are smaller than average in some people with schizophrenia

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

Specific types of therapy may reverse or prevent these changes

Eack et al, Arch Gen Psych 2010

Eack et al, Arch Gen Psych 2010

And lead to improvements in social and cognitive functioning

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

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

Controls People 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

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 > Dp < .05p < .05

B.A.

*

*

CON ND D

**

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 delusionsND = people with schizophrenia without delusions

CON = controls

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

One example: there is reduced communication between two cortical areas (within the cingulate gyrus) in schizophrenia

0.15

1.0

Cor

rela

tion

(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

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

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

= 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 C677T effects on prefrontal activity during working memory

Roffman et al, PNAS 2009

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

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

The Future:Decreasing cost, increasing throughput of genotyping over time

Taqman (1)

SBE-FP (1)

Affymetrix (500K)

Sequenom Mass Spec (5)

Illumina (1536)

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

1mm

Thank you for your attention!

Questions?