Mechanisms and Regulation of 5-HT Receptors in the CNS

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¿¿¿¿¿The¿neurotransmitter¿serotonin¿is¿thought¿to¿have¿broad¿functions¿in¿the¿central¿ nervous¿system,¿contributing¿to¿the¿biological¿basis¿underlying¿both¿behavior¿and¿ cognition.¿This¿neurotransmitter¿has¿also¿been¿implicated¿in¿mental¿disorders,¿ especially¿anxiety¿and¿depression,¿and¿several¿pharmacological¿agents¿used¿to¿treat¿ these¿diseases¿target¿serotonergic¿systems¿in¿the¿brain.¿¿ ¿¿¿¿¿Serotonin¿acts¿through¿multiple¿serotonin¿receptors¿to¿regulate¿neuronal¿activity¿and¿ work¿during¿the¿last¿decade¿has¿made¿extraordinary¿advances¿in¿our¿understanding¿of¿ the¿basic¿biology¿of¿these¿receptors.¿However¿our¿understanding¿of¿how¿these¿receptors¿ function¿within¿neurons,¿what¿they¿signal¿and¿how¿they¿signal¿in¿the¿central¿nervous¿ system,¿is¿still¿poorly¿understood.¿This¿is¿an¿important¿lacunae,¿since¿the¿biological¿ basis¿of¿mental¿disorders,¿as¿well¿as¿the¿development¿of¿better¿treatments,¿will¿be¿ grounded¿in¿the¿specific¿mechanisms¿used¿by¿these¿receptors.¿ ¿¿¿¿¿The¿long¿term¿goal¿of¿the¿PI's¿research¿program¿is¿to¿help¿develop¿a¿mechanistic¿ understanding,¿at¿the¿molecular¿level,¿of¿serotonin¿receptor¿function¿in¿central¿nervous¿ system¿neurons.¿Specifically¿in¿this¿application¿we¿propose¿to¿use¿a¿synergistic¿ combination¿of¿electrophysiological¿and¿molecular¿biological¿approaches¿to¿understand¿ the¿signaling¿mechanisms¿used¿by¿5HT2A¿receptors¿in¿the¿cerebral¿cortex.¿¿ ¿¿¿The¿application¿proposes¿three¿Specific¿Aims.¿The¿first¿of¿these¿will¿elucidate¿the¿ proximal¿signaling¿mechanism¿used¿by¿5HT2A¿receptors¿to¿regulate¿membrane¿ excitability¿in¿pyramidal¿cells¿of¿the¿prefrontal¿cortex.¿The¿second¿Aim¿will¿test¿the¿idea¿ that¿5HT2A¿receptors¿inhibit¿the¿slow¿calciumactivated¿potassium¿current¿present¿in¿ pyramidal¿cells¿by¿reducing¿the¿concentration¿of¿membrane¿PtdIns(4,5)2.¿The¿third¿ Specific¿Aim¿will¿determine¿how¿5HT2A¿receptors¿depolarize¿and¿excite¿pyramidal¿ cells.¿¿ ¿¿¿The¿results¿of¿this¿project¿should¿contribute¿to¿our¿understanding¿of¿serotonergic¿ mechanisms¿in¿the¿brain¿and,¿as¿such,¿contribute¿to¿our¿understanding¿of¿mental¿ disorders¿while¿supporting¿the¿search¿for¿more¿effective¿treatments.¿ The¿neurotransmitter¿serotonin¿has¿been¿implicated¿in¿the¿genesis¿of¿anxiety¿and¿ depression¿and¿in¿the¿mechanism¿of¿action¿of¿several¿drugs¿effective¿in¿the¿treatment¿of¿ mental¿disorders.¿The¿research¿proposed¿in¿this¿application¿seeks¿to¿elucidate¿the¿ molecular¿mechanisms¿used¿by¿serotonin¿to¿regulate¿the¿function¿of¿brain¿cells¿and¿ brain¿circuits.¿The¿results¿of¿this¿project¿should¿help¿us¿better¿understand¿mental¿ disorders¿and¿contribute¿to¿the¿search¿of¿more¿effective¿treatments.¿