GABAergic Molecular Pathology in Bipolar Disease

GABAergic Molecular Pathology in Bipolar Disease

 

  1. Davis, A. Guidotti, D. Grayson, P. Tueting, and E. Costa

 

Psychiatric Institute, University of IL at Chicago, Chicago, IL 60612

 

 

We suggest that prefrontal cortex (PFC) GABAergic interneurons are a target of investigation into the molecular pathology of bipolar illness.  We suggest that the same process is also involved in schizophrenia and that this part of the molecular pathology is shared by these two disorders.  We suggest that one of the elements in the process is an abnormality, reelin.  Certain GABAergic neurons release reelin which act on inegrin receptors located on dendritic spine postsynaptic densities.  Both reelin and GAD67 is reduced in the PFC GABAergic neurons of bipolar patients and schizophrenics but not unipolar depressed patients or normal controls due to downregulation of reelin and GAD67mRNA.  We suggest that this is a result of increase expression in GABAergic neurons of DNA-(cytosine 5)-methyltransferase 1 (DNMT1) that contributes to the epigenetic hypermethylation of CpG island and promoters expressed in reelin and GAD67 genes, leading to a decrease synthesis of the two gene transcripts.  We feel this may lead to a decrease in the number of synaptic spines and other GABAergic neuropathology found in bipolar disease and schizophrenia.  This decrease may be a factor for the decrease in grey mater and increase in ventricle sizes also seen in these diseases