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 Section
of Molecular and Clinical Neurobiology
Head: Dan Rujescu
Scientific members: Ina Giegling, Annette Hartmann, Just Genius, Jens
Benninghoff
The Section emerged 2004 form the Molecular and Clinical Neurobiology
Group, which was founded in 1997. It consists of a multidisciplinary
team with several areas of expertise: Ina Giegling has a major interest
in human genetics and intermediate phenotypes, Annette Hartmann is
specialized in genetics and molecular neurobiology, Just Genius is
focused on cellular neurobiology and histology, and Jens Benninghoff’s
interest is in adult stem cell biology. Additionally, Hans-Joachim Kuss
is conducting HPLC-based studies. The Section follows a multidimensional
translational approach to neuropsychiatric diseases and behavioral
phenotypes at genetic, molecular, cellular, structural, functional,
cognitive and behavioral levels, and also integrates animal and cellular
models. It is involved in extensive academic and industrial national and
international genome and post-genome efforts on neuropsychiatric
diseases and behavioral phenotypes. A variety of neurobiological methods
have been established including high-throughput genotyping,
allele-specific RNA expression analysis, microarray-based RNA expression
techniques, protein quantification, neuronal and stem cell cultures
including a variety of assays for cell viability, proliferation,
differentiation, migration, apoptosis, reactive oxygen species, Ca2+
fluxes, as well as post mortem and behavioral studies in rodents.
The major focus is on the genetics
and neurobiology of neuropsychiatric diseases and behavioral phenotypes,
especially of schizophrenia, cognition, aggression, suicide and
addiction. A multidimensional translational approach which involves
recruitment and extensive phenotyping of large samples, high throughput
genotyping, and cellular and animal models is implied.
Dan Rujescu is also co-director of the Genetics Research Centre (GRC), a
joint biotech initiative between LMU and GSK, which provides
high-throughput genotyping for SNP validation and association studies
employing both pooled and individual DNA samples.
Genetics of Schizophrenia and
Intermediate Phenotypes
There is evidence for a strong genetic component in the etiology of
schizophrenia, as demonstrated by family, twin and adoption studies. The
risk of developing the disease increases exponentially with the genetic
relatedness to an individual suffering from the disorder. In comparison
with the 1% risk for schizophrenia in the general population,
third-degree relatives carry an approximate 2% chance of developing
schizophrenia, and the risk increases to 9% in first-degree relatives.
Moreover, in identical (MZ) twins the concordance rate is approximately
50%. Adoption studies provide strong evidence that the familial
aggregation is not the result of shared environmental factors, as
individuals adopted into families containing an affected individual do
not suffer an increased risk of developing schizophrenia, whereas the
existence of a biological relative with schizophrenia does lead to an
increased risk in adoptees. The relative contribution of genetic factors
in the etiology of schizophrenia has been estimated to be approximately
80%. The mode of inheritance is complex and non-Mendelian, involving the
combined action of several genes, each of which might account for only a
small increase or decrease in susceptibility to the disorder. To
identify schizophrenia susceptibility genes, we recruited a large number
of extensively phenotyped schizophrenic patients, relatives and healthy
controls for linkage-, genetic case-control-, and whole genome
association studies.
A complementary approach to the genetics of schizophrenia is to use
endophenotypes. The rationale for their use in gene discovery is that
endophenotypes associated with a psychiatric disorder are more
elementary compared to clinical phenotypes. This also implies that the
number of genes required to produce variations in these traits may be
fewer than those involved in producing a psychiatric diagnostic entity.
Our endophenotype project includes a broad range of schizophrenia
endophenotypes. These comprise, among others neuropsychological
parameters (e.g. working memory, attention/vigilance, verbal learning
and memory, visual learning and memory, speed of processing, reasoning,
problem solving and antisaccades). Extensive academic and industrial
national and international genome and post-genome collaborations have
been initiated to understand the genetics and pathophysiology of
schizophrenia and intermediate phenotypes.
Molecular and Cellular
Neurobiology
We established an NMDA receptor antagonist animal model which mimics
several aspects of psychosis to identify further candidate genes which
can be used in our human studies. In our model, chronic, low-dose
treatment with MK801 alters the expression of NMDA receptor subunits in
a pattern similar to schizophrenia on the molecular level. On a cellular
level, the number of parvalbumin-positive interneurons was decreased, a
finding which parallels observations in post mortem brain from
schizophrenic patients. On a functional level, recurrent inhibition of
pyramidal cells was altered, as postulated from the histological
findings. Finally, on a behavioral level these animals showed cognitive
deficits like disturbed working memory, which again parallels findings
in schizophrenia. We used a functional genomic approach for the
identification of hippocampal candidate genes for psychosis-related
traits and identified several differentially expressed genes and
pathways. Furthermore, genetically manipulated mice are used to further
characterize disease-related genes. A variety of neurobiological methods
is established including allele-specific RNA expression analysis,
microarray-based RNA expression techniques, protein quantification,
adult stem and neuronal cell cultures including assays for cell
viability, proliferation, differentiation, migration, apoptosis,
reactive oxygen species, Ca2+ fluxes, as well as behavioral studies in
rodents. These techniques have been extensively used to e.g. understand
the physiology of adult stem cells in health and disease and to
elucidate the role of glutamatergic neurotransmission and oxidative
stress in schizophrenia.
Pharmacogenetics
Beside genetics, endophenotypes and neurobiology, pharmacogenetics and
pharmacogenomics of antipsychotics are another focus. A large
pharmacogenetic study on response to antipsychotics was conducted. The
fact that dopamine receptors are the primary targets of current
antipsychotics prompted the investigation of genes involved in dopamine
neurotransmission in response to treatment. Furthermore, this ongoing
study investigates the association of response to antipsychotics with a
high number of microsatellites and SNPs in various genes selected based
on their role in neurotransmission and differential gene expression in
own animal models.
Genetics of Suicidal Behavior
and Personality Traits
Suicidal behavior is a major health problem worldwide. The risk of
suicide-related behavior is supposed to be determined by a complex
interplay of sociocultural factors, traumatic life experiences,
psychiatric history, personality traits, and genetic vulnerability. This
view is supported by adoption and family studies indicating that
suicidal acts have a genetic contribution which is independent of the
heritability of Axis I and II psychopathology. The heritability for
serious suicide attempts was estimated to be 55%. The Section conducted
a series of molecular genetic studies on suicidal behavior and
personality traits (i.e. aggression, impulsivity, neuroticism) as risk
factors for suicidal behavior. Microarray- and qPCR-based RNA expression
studies were conducted to identify differentially expressed genes in the
orbitofrontal cortex of suicide victims which were used in genetic
association studies.
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