In our previous funding period, we studied the SHTiA receptors and the receptor-linked phosphoinositide signaling system (PI) in the postmortem brain of suicide victims and some of the major findings are: 1) The protein and mRNA expression levels of various isozymes of protein kinase C (PKC) were decreased and 5HT2A receptor binding as well as protein and mRNA expression were increased in PFC and hippocampus of teenage suicide victims. Similarly, protein and mRNA expression of some specific isozymes of PKA, CREB, and BDNF were altered in the postmortem brain of suicide victims. These findings were quite interesting and important and therefore warrant further investigation as to their significance and their effects on functional responses in suicide brain. The major objective of the proposed research in the competing continuation application is to study the cellular and molecular mechanisms associated with suicidal behavior and to further examine the functional consequences of the observed increase in the 5HT2A receptors and of the decrease in PKC. PKC interacts with other signaling systems, such as the WNT pathway and the GABAergic system. These signaling systems have also been implicated in the pathophysiology of mood disorders and possibly suicide. In the proposed application, we plan to determine the various components of the PI and the WNT signaling pathways, GABAA receptors, and the enzymes GAD. These studies will be performed in the PFC and hippocampus of adult and teenage suicide victims. More specifically, we will determine in Specific Aim 1 the enzyme PLD, the IPs receptors, calcium-independent PKC isozymes, and the transcription factor CREB.
In Specific Aim 2, we propose to study the WNT pathway, and will determine GSK-3beta and beta-catenin, which are important components of the WNT pathway, calcineurin and the transcription factor NFAT, which are involved in the transcription of IPs receptors.
In Specific Aim 3, we propose to study the GABA-synthesizing enzymes GADes and GADe? as well as the key GABAA receptor subunits. These studies are based on our general hypothesis that certain components of the PI signaling system and the WNT pathway are altered in the postmortem brain of suicide victims. Some of these abnormalities may be similar as well as dissimilar between adult and teenage suicide victims. These studies will provide further knowledge about the pathophysiology of adult and teenage suicide and may also indicate the specific sites of these abnormalities. This knowledge may aid in developing better therapeutic strategies for the treatment of suicidal behavior.
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