© Copyright 2000 Physicians Postgraduate Press, Inc. One personal copy may be printed 21 J Clin Psychiatry 1999;60 (suppl 2) MARCKS Expression and Suicide uicide is a leading cause of death in the United States and is commonly associated with mood disorders, Expression of the Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) and MARCKS-Related Protein (MRP) in the Prefrontal Cortex and Hippocampus of Suicide Victims Robert K. McNamara, Ph.D.; Thomas M. Hyde, M.D., Ph.D.; Joel E. Kleinman, M.D., Ph.D.; and R. H. Lenox, M.D. Background: Although suicide is a leading cause of death in the United States and represents a significant public health threat, little is known about the neurobiological or molecular factors that con- tribute to its pathophysiology. A number of studies now indicate that lithium has considerable efficacy in the prevention of suicide in patients with affective disorders, and accumulating evidence indicates that protein kinase C (PKC) and its substrates, in particular the myristoylated alanine-rich C kinase substrate (MARCKS), are primary targets of chronic lithium treatment. We therefore hypothesized that a dysregulation in MARCKS expression in key brain regions could contribute to the pathophysi- ology associated with suicide. To address this, we examined MARCKS, as well as the closely related MARCKS-related protein (MRP), mRNA expression in the hippocampus and dorsolateral prefrontal cortex of suicide victims and normal controls. Method: MARCKS and MRP mRNA expression was assessed by quantitative in situ hybridization histochemistry performed on postmortem hippocampal and dorsolateral prefrontal cortex sections from suicide (N = 9) and normal control (N = 10) brains. Results: In the normal hippocampus, both MARCKS and MRP mRNA expression were highest in the granule cell layer and low-moderate in CA1, CA3, and hilus. A high level of MRP mRNA expression was also observed in the white matter of the fimbria/fornix. Neither MARCKS nor MRP mRNA ex- pression levels differed significantly in the granule cell layer, CA3, hilus, or CA1 in suicide victims relative to normal controls (1-way ANOVA, p > .05). In the normal prefrontal cortex, MARCKS was expressed exclusively in gray matter (layers I–VI), whereas MRP was expressed in both gray and white matter. Neither MARCKS nor MRP mRNA expression levels in the gray and white matter re- gions of the dorsal prefrontal cortex differed between suicides and normal controls (1-way ANOVA, p > .05). Conclusion: The present findings are the first to demonstrate the expression and distribution of MARCKS and MRP in the human hippocampus and dorsolateral prefrontal cortex, and their ex- pression pattern within these regions bears strong resemblance to those observed in the adult rat brain. Comparison of MARCKS and MRP mRNA expression in the hippocampus and prefrontal cortex of suicide victims and normal controls indicates that these 2 mRNAs are not differentially regulated in these regions. However, differences in MARCKS and MRP protein expression and function cannot be ruled out by the present findings. (J Clin Psychiatry 1999;60[suppl 2]:21–26) From the Department of Psychiatry, University of Pennsylvania School of Medicine, Abramson Research Center, Philadelphia (Drs. McNamara and Lenox), and the Neuropathology Section, Clinical Brain Disorders Branch, IRP/NIMH/NIH, Bethesda, Md. (Drs. Hyde and Kleinman). Research supported in part by a grant from The Stanley Research Foundation (Drs. Lenox and McNamara). Presented at the symposium “Effects of Medical Interventions on Suicidal Behavior,” which was held February 26–28, 1998, Miami, Fla., cosponsored by the American Foundation for Suicide Prevention, the Johns Hopkins University School of Medicine, and the Long Island Jewish Medical Center, with the cooperation of the Suicide Prevention Advocacy Network, and supported by an educational grant from Solvay Pharmaceuticals, Inc. Reprint requests to: Robert H. Lenox, M.D., University of Pennsylvania School of Medicine, Department of Psychiatry, Abramson Research Center (Rm 802), 34th and Civic Center Blvd., Philadelphia, PA 19104 (e-mail: rlenox@ mail.med.upenn.edu). S particularly major depression and manic-depressive disor- ders. 1–3 This significant public health threat therefore ne- cessitates an understanding of the risk factors that predis- pose a person to suicidal behavior so that better diagnostic criteria and effective treatment and prevention strategies can be developed. Studies over the past several years have provided increasing evidence for a neurobiological basis for suicidal behavior. 4 Altered regulation of serotonin neu- rotransmission in critical regions of the limbic system and prefrontal cortex is a prominent example of a biologically based risk factor for impulsive behaviors including sui- cide. 5,6 In addition, the results of family, twin, and adop- tion studies suggest a significant genetic contribution to