Biological and Molecular Psychiatry

Biological and Molecular Psychiatry
Head of the lab:
Prof. Abraham Weizman, MD and Prof. Gil Zalsman MD
Phone: 03-9376275
Lab Manager:
Dr. Miri Carmel, Ph.D
Phone: 03-9258205
Research team:
    Dr. Shay Horenfeld, Ph.D    
    Prof. Amir Krivoy, MD    
    Dr. Eldar Hochman, MD    
Research Areas:
Our laboratory focuses on the neurobiology and the contribution of genes and environment interaction to the pathophysiology of severe mental disorders, including eating disorders, OCD, Tourette's disorder, major depression, suicidal behavior and schizophrenia. In addition, we assessed the role of genetic variants in the response of depressed/anxious children and adolescents to antidepressants using a pharmacogenetic approach.

We have a long-standing interest in the association between 22q11.2 deletion syndrome (22q11.2DS) and psychiatric manifestations, especially schizophrenia spectrum disorders, since this copy number variation (CNV) is the highest known risk factor for schizophrenia (30% develop schizophrenia in adulthood). We search for genetic variants within the 22q11.2 deletion region as well as in the whole genome and epigenome that may contribute to the neuropsychiatric phenotypes in 22q11.2DS.

To this end we use a variety of molecular and bioinformatic approaches, including identification of de novo and hereditary mutations (CNVs, SNVs and ins/del), analyses of whole exome sequencing (WES), comparative genomic hybridization (CGH) array, epigenome-wide association study (EWAS) and transcriptome screening (Figures 1-4).
In addition to the neurobehavioral/neuropsychiatric manifestations individuals with 22q11.2DS exhibit immunological abnormalities that make this syndrome an appropriate genetic model for studying effect of the immune system on psychosis development (Figure 5).

The relationship between the immune system and the brain were assessed by the involvement of neuroinflammatory factors in the pathophysiological mechanisms leading to neuropsychiatric disorders, including schizophrenia and mood disorders. In addition, we evaluate the relationship between abnormalities in the immune-endocrine system and major depression and drug abuse.

Among the most important prognostic factors of people suffering from schizophrenia is the adherence to treatment and response to antipsychotic compounds. About third of the psychotic patients do not respond to antipsychotics and two thirds of them will benefit from clozapine treatment. We attempt to identify the biological pathways of response and resistance to antipsychotic compounds, and especially to clozapine. We employ various research methods to study both human samples and animal models of psychosis.

Recent evidence has associated mood disorders with blood-brain barrier (BBB)/neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin-4 (AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigate the effects of lithium on BBB integrity and NVU-related protein expression in chronic mild stress (CMS)-rat model of depression (Figure 6) and in human subjects with major depression.

In collaboration with Dr. Konstantin Bloch from the FMRC we investigate novel cellular treatment of metabolic dementia in a mouse model (Figure 7).

In collaboration with Prof. Moshe Gavish from the Technion we investigate the role of TSPO (translocator protein) in inflammation and brain diseases and we developed liposomal treatments for brain diseases.

Fig. 1-2 Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia: a genealogical molecular approach (Michaelovsky E*, Carmel M* et al, 2019 Transl Psych)

Fig. 3-4 Differential methylation of imprinting genes and MHC locus in 22q11.2 deletion syndrome-related schizophrenia spectrum disorders (Carmel M*, Michaelovsky E* et al, 2020 World J Biol Psychiatry)

Fig. 5 Mean CRP levels for psychotic 22q11.2DS vs. non psychotic 22q11.2DS vs. controls Elevated proinflammatory markers in 22q11.2 Deletion Syndrome are associated with psychosis and cognitive deficits (Mekori-Domachevsky E. et al, 2017 J Clin Psychiatry)

Fig. 6 Chronic mild stress and lithium treatment regulate hippocampal Aquaporin-4 (AQP4) expression Regulatory effect of lithium on hippocampal blood-brain barrier integrity in a rat model of depressive-like behavior (Taler M. et al, 2020 Bipolar Disord)

Fig.7 Characteristics of grafted islets in icv-STZ rats Grafted islets located onto the cerebral cortex: H&E staining (D), insulin, glucagon and DAPI staining (E), proinsulin, Glut2 and DAPI staining (F). Long-term effects of intracranial islet grafting on cognitive functioning in a rat metabolic model of sporadic Alzheimer’s disease-like dementia (Bloch K et al, 2020 Plos One)

Contact details
Carmel Miri Lab Phone: 03-9376275 Mobile: 052-6488798
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