Stella Plevan

Research

Research

Specific Clinical/Research Interest:
1. Role of Serotonin 2C Receptor mRNA Editing in Psychiatric Conditions (Suicide, Drug Addiction) 2. Molecular Abnormalities in the Brain of Schizophrenia Patients
Current Students: Rebecca Lyddon
Research Personnel: Kevin Wong, Nayna Patel
My research interests center around the neurobiology and the neurochemistry of several psychiatric conditions including suicide and drug addiction. Specifically, we are investigating the role of serotonin 2C receptor (5-HT2CR) heterogeneity in these pathological states. The 5-HT2CR is encoded by a single gene (HTR2C) but it is expressed as numerous isoforms in brain. One of the sources of the receptor diversity is an editing of its mRNA by hydrolytic deamination that involves conversion of adenosine to inosine. Editing of the 5-HT2CR mRNA takes place at five closely spaced adenosines of the HTR2C mRNA located within a sequence encoding the putative second intracellular domain of the protein -- a region thought to be of general importance for G protein coupling. Because inosines are read as guanosines by the cell's translational machinery, the editing can alter the coding potential of three triplet codons and allows for the generation of 24 different protein isoforms wh! ich vary significantly in their agonist-induced and constitutive activity. In rodent and human brain, a mixture of differently edited and non-edited 5-HT2CR mRNAs has been reported. 5-HT2CR and suicide: Results from a large number of studies have implied that a predisposition of people to suicidal behavior is strongly associated with both psychiatric disease and impaired serotonergic function. The serotonergic involvement with suicide appears to be equally strong, regardless of the associated psychiatric disorder. Therefore, brain serotonergic abnormalities may constitute a common basis for suicidal behavior irrespective of the underlying psychiatric illness. The precise nature of serotonergic defects in suicide remains elusive, however. The 5-HT2CR is a plausible candidate which might contribute to suicidal behavior because it has been shown to be widely distributed in the central nervous system and is thought to play an important role in regulating mood and affect. We are currently investigating whether the editing of 5-HT2CR is altered in the victims of suicide compared to people who died by other causes. 5-HT2CR and drug addiction: A large body of evidence supports the hypothesis that 5HT2CRs that are expressed in the ventral tegmental area (VTA) modulate the basal activity of the dopamine (DA) midbrain neurons through the enhancement of the GABAergic inhibitory neurotransmission, and subsequently, control the rewarding effects of psychostimulants and other drugs of abuse (e.g. ethanol and nicotine). Thus, it is plausible that differences in 5-HT2CR function in VTA influence individual differences in sensitivity to drugs of abuse. In our future studies we are planning to investigate whether an individual's repertoire of the 5-HT2CR isoforms may underlie phenotypic differences in responsivity to drugs of abuse and perhaps predisposition to addiction in rodents and humans.