Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE KOMUROLABORATORYCOLLABORATORSArmando A. Genazzani, Ph.D. 1Pasko Rakic, M.D., Ph.D. 21Dept. of Pharmacol., Univ. ofCambridge, UK2Sect. of Neurobiology,Yale Univ. Sch. of Med.,New Haven, CTThe long-term goal of our laboratory is toelucidate the cellular and molecularmechanisms underlying neuronalmigration in the developing brain.(1) At present, we are determiningwhether somatostatin, a neuropeptide, controlsthe transition of cerebellar granule cell migrationduring the translocation from the cells’ birthplaceto their final destination. We are determiningcharacteristic features of the migratingbehavior of granule cells in their natural cellularmilieu with the use of confocal microscopy andacute slice preparationsobtained from the earlypostnatal mouse cerebellum.We will determine whetherand how activation and/orinhibition of somatostatinreceptors affect the granulecell’s behavior and itsmorphology in each cerebellarcortical layer. Furthermore,we will determine howintracellular messengers,including Ca 2+ and cAMP,which are modified byactivation of somatostatinreceptors, differentiallyregulate the behavior of thecell body and the process ofmigrating granule cells.Transient expression ofsomatostatin and its receptorsis a characteristic feature ofdeveloping neurons duringperiods of neurogenesis and brain differentiation.The function of somatostatin in neuronalmigration, however, is not known. Answers tothese questions will elucidate the undiscoveredrole of somatostatin and its receptors in theformation of brain and provide new insights forunderstanding the effects of various genetic andenvironmental factors in the pathogenesis ofbrain malformations that are implicated invariety of functional disorders, such as epilepsy.(2) Maternal alcohol consumption duringpregnancy can cause serious birth defects, ofThe Department of NeurosciencesCellular Mechanisms UnderlyingCerebellar Granule Cell Migrationwhich fetal alcohol syndrome (FAS) is the mostdevastating. Recognized by characteristiccraniofacial abnormalities and growth deficiency,this condition includes severe alcohol-induceddamage to the developing brain. FAS childrenexperience deficits in intellectual functioning anddifficulties in learning, memory, problem-solving,and attention; problems with mental health andsocial interactions also affect these children.In our laboratory, to elucidate the cellularand molecular mechanisms underlying alcoholinducedmalformation of brain, we are determiningthe effects of alcohol oncerebellar granule cell migration.First, we will determine when,where and how alcohol altersthe migration of cerebellargranule cells in real time withthe use of acute cerebellar slicepreparations and microexplantcultures. In particular, we willexamine the relationshipbetween the amounts anddurations of alcohol administrationand the inhibition of cellmovement. Second, we willdetermine whether changes inintracellular Ca 2+ fluctuationsand the membrane potential ofmigrating granule cells areinvolved in alcohol-inducedalteration of neuronal migration.Third, we will determineHitoshi Komuro, Ph.D. whether manipulations ofintracellular Ca 2+ fluctuationsand membrane potentials by activating NMDAreceptor or inhibiting K + channel activity canovercome the alcohol-induced changes in cellmigration.The fundamental mechanisms wherebyethanol administration leads to disturbances inbrain development have not been delineateddefinitively. Answers to the questions raised in thisproject will provide new insights for postnataltreatments and understanding how prenatal andearly postnatal exposure to alcohol causesmalformation of brain.Kumuro, H., Yacubova, E., and P. Rakic (2001) Mode and tempo of tangential cell migration in the cerebellar externalgranular layer. J. Neurosci. 21:527-540.Yacubova, E., and H. Komuro (2002) Stage-specific control of neuronal migration by somatostatin. Nature 415:77-81.Yacubova, E., and H. Komuro (2002) Intrinsic program for migration of cerebellar granule cells in vitro. J. Neurosci.22:5966-5981.Yacubova, E., and H. Komuro (2003) Cellular and molecular mechanisms of cerebellar granule cell migration. Cell.Biochem. Biophys. 37:213-234.Komuro, H., and E. Yacubova (2003) Recent advances in cerebellar granule cell migration. Cell. Mol. LifeSci.60:1084-1098.138