Attenuated 5-HT 1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase Shu-chi Hsiung,* Mella Adlersberg,* Victoria Arango,* ,   , à J. John Mann,* , à Hadassah Tamir* ,   , à and Kuo-peing Liu* *Department of Neuroscience, New York State Psychiatric Institute, New York, USA Departments of  Anatomy and Cell Biology and àPsychiatry, Columbia University, College of Physicians and Surgeons, New York, New York, USA Abstract Positron emission tomography studies in major depression show reduced serotonin (5-HT) 1A receptor antagonist-binding potentials in many brain regions including occipital cortex. The functional meaning of this observation in terms of signal transduction is unknown. We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of 5-HT 1A receptor activation. The diagnosis was established by means of psychological autopsy using Diag- nostic and Statistical Manual of Mental Disorders (DSM) III-R criteria. Measurements of [ 35 S]GTPcS binding to Gai/o in the occipital cortex of suicide victims and matched controls re- vealed a blunted response in suicide subjects and a decrease in the coupling of 5-HT 1A receptor to adenylyl cyclase. No significant group differences were detected in the expression levels of Gai/o, Gaq/11 or Gas proteins, or in the activity of cAMP-dependent protein kinase A. Studies of a parallel transduction pathway downstream from 5-HT 1A receptor activation demonstrated a decrease in the activity of phos- phatidylinositol 3-kinase and its downstream effector Akt, as well as an increase in PTEN (phosphatase and tensin homolog deleted on chromosome 10), the phosphatase that hydrolyzes phosphatidylinositol 3,4,5-triphosphate. Finally, the activation of extracellular signal-regulated kinases 1 and 2 was attenuated in suicide victims. These data suggest that the alterations in agonist-stimulated 5-HT 1A receptor activation in depressed suicide victims are also manifest downstream from the associated G protein, affecting the activity of second messengers in two 5-HT 1A receptor transduction pathways that may have implications for cell survival. Keywords: adenylyl cyclase, Akt, G protein, mitogen-activa- ted protein kinase, phosphatidylinositol 3-kinase, suicide. J. Neurochem. (2003) 87, 182–194. Although several findings indicate that levels of the neuro- transmitter serotonin (5-HT) are reduced in depressed suicide victims (Mann 1998), the physiological consequences of such a reduction for 5-HT-receptor-activated downstream signaling are less well described. Autoradiographic studies on brains obtained from suicide victims revealed an increased density of postsynaptic 5-HT 1A receptor agonist Received April 30, 2003; revised manuscript received June 20, 2003; accepted June 20, 2003. Address correspondence and reprint requests to Hadassah Tamir, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. E-mail: ht3@columbia.edu Abbreviations used: AC, adenylyl cyclase; PDK, phosphatidylinositol- dependent kinase; PIP 2 , phosphatidylinositol 4,5-biphosphate; BSA, bovine serum albumin; cAMP, cyclic AMP; DTT, dithiothreitol; ERK, extracellular signal-regulated kinase; GSK-3a/b, glycogen synthase kinase-3; HRP, horseradish peroxidase; 5-HT, serotonin; IBMX, iso- butylmethylxanthine; MAP kinase, mitogen-activated protein kinase; MDD, major depressive disorder; 8-OH-DPAT, (+/–)-8-hydroxy-dipro- pylaminotetralin; PFC, prefrontal cortex; PI3-K, phosphatidylinositol 3- kinase; PI3-P, phosphatidylinositol 3-phosphate; PIP 3 , phosphatidy- linositol 3,4,5-triphosphate; PKA, protein kinase A; PTEN, phosphatase and tensin homolog deleted on chromosome 10, also called MMAC1 or TEP1; PTX, pertussis toxin; SDS, sodium dodecylsulfate; WAY-100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohex- anecarboxyamide. Journal of Neurochemistry , 2003, 87, 182–194 doi:10.1046/j.1471-4159.2003.01987.x 182 Ó 2003 International Society for Neurochemistry, J. Neurochem. (2003) 87, 182–194