Special Lecture

  1. Special Lecture
  2. Clinical Research Educational Seminar
  3. Symposiums
  4. Prize for encouragement of the society
  5. Abroad
  6. Lunceon Seminar
  7. Evening Seminar
  8. Oral Abstracts
  9. Poster Abstracts

SL-1

Schizophrenia, impaired reality testing and the AHI1 gene: From men to mice

Bernard Lerer1, Tzuri Lifschytz1, Alexandra Slonimsky1, Suzan Abedat2, Yakov Fellig3, Hagit Cohen4, Gadi Goelman5, Amit Lotan1

  1. Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem
  2. Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem
  3. Dept of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem
  4. Mental Health Center, Beersheba
  5. MRI Lab, Medical Biophysics, Hadassah-Hebrew University Medical Center, Jerusalem; Israel

Objectives
The Abelson helper integration site (AHI1) gene plays a pivotal role in brain development. Loss of function mutations cause Joubert Syndrome, a severe neurodevelopmental disorder. Studies by our group, replicated by others, have demonstrated association of AHI1 with susceptibility to schizophrenia and altered expression of AHI1 in lymphoblasts from early onset schizophrenia patients. We sought to elucidate the mechanism whereby alteration in the AHI1 expression may be implicated in the pathogenesis of schizophrenia.

Methods
We compared the performance of mice heterozygous (Ahi1+/-) for an Ahi1 knockout mutation as compared to wild type (Ahi1+/+) littermates on behavioral tests that model cognitive, negative and positive aspects of schizophrenia and on tests reflecting anxiety. Serum cortisol and core body temperature were measured following behavioral and pharmacological experiments. We sought structural abnormalities in the brains of Ahi1+/- mice and have begun to dissect neural circuits through the use of functional connectivity imaging during resting state (rsfMRI).

Results
RT-PCR revealed lower expression of Ahi1 mRNA in Ahi1+/- mice. Western blots showed significantly lower Ahi1 protein levels in Ahi1+/- newborns. Behavioral testing did not reveal abnormalities of Ahi1+/- mice on measures reflecting cognitive function and positive or negative schizophrenia symptoms. However, significantly lower levels of situational anxiety were a strong and consistent finding. Serum cortisol levels and core body temperature were significantly lower in Ahi1+/- mice after exposure to situationaly provoked anxiety. To establish whether the ability of Ahi1+/- mice to "feel" anxiety is different from that of Ahi1+/+ mice, we measured serum cortisol levels after anxiogenic challenge with caffeine and acoustic startle. Cortisol levels were not different in Ahi1+/- and Ahi1+/+ mice. No abnormalities in brain volume were observed in Ahi1+/- mice in adulthood on T2-weighted MRI; light microscopy revealed normal cytoarchitecture. However, preliminary rsfMRI data indicate that significant connections in Ahi1+/+ mice, such as those involving the neocortex, cerebellum and amygdala are diminished in Ahi1+/- mice.

Conclusion
Our findings indicate that reduced expression of Ahi1 in mice is associated with a decrease in perception of threatening situations that is putatively analogous to impaired reality testing in humans. It is noteworthy that Ahi1+/- mice manifest a similar degree of anxiety to Ahi1+/+ mice, reflected in serum cortisol level, on exposure to caffeine challenge and acoustic startle. Reduced threat detection, as manifested by Ahi1+/- mice, may arise from reduced connectivity between the amygdala and other forebrain areas, including the cortex. This finding has been reported in schizophrenia and autism and is consistent with neurodevelopmental theories of schizophrenia.

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SL-2

Advances of pharmacogenetics in psychiatry

Min-Soo Lee

Department of Psychiatry, Korea University College of Medicine, Seoul, Korea

For establishment of predictor for individual treatment outcomes by psychotropic drugs, pharmacogenetics has been in the limelight over the past few decades. Although data accumulated from the approaches have provided us with the understandings of genetic backgrounds for individual differences in treatment response and have successfully offered cornerstones of recent advances in pharmacogenetics, the many of them are still controversial due to the lack of replication derived from ethnic differences of therapeutic responses, allele frequencies or LD structure, differences of phenotype definitions and the use of various drugs. The recent efforts in pharmacogenetics have been focused on to overcome these limitations by studying genome-wide association, gene-gene or gene-environment interaction and comparison between drugs. In addition, genetic approaches have been merging into other research field such as brain imaging. These advances are growing discernment for complex traits of individual differences in treatment outcomes, and some of them seem to be successful and significant for clinical application. This short review will deal with conventional pharmacogenetic approaches and their limitations, summarize recent efforts made for establishing more accurate genetic markers, and suggest a direction to which pharmacogenetic study would advance.

 

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  1. Special Lecture
  2. Clinical Research Educational Seminar
  3. Symposiums
  4. Prize for encouragement of the society
  5. Abroad
  6. Lunceon Seminar
  7. Evening Seminar
  8. Oral Abstracts
  9. Poster Abstracts