Abstract

PROJECTABSTRACT Inmesialtemporallobeepilepsy(TLE),aninitialprecipitatingeventtriggersaprogressiveprocessof celldeathandcircuitreorganizationthatrendersneuralnetworkshyperexcitableandsusceptibletoabnormal synchronizedactivitythatmanifestsasspontaneousrecurringseizures.TLEisoneofthemostcommonand difficulttotreatformsoffocalepilepsyandisassociatedwithhippocampalneurodegenerationthatsparesthe CA2region.Inchronicallyepilepticanimalsseizurespropagatethroughthehippocampusdespitewidespread celldeathinCA1andCA3,suggestingthatepilepticactivitymaybegeneratedinorconveyedthrough survivingCA2circuitry.Furthermore,accumulatingevidencesuggeststhatCA2mayhaveanimportantrole controllinghippocampalnetworkexcitabilityandsynchrony,buttheunderlyingmechanismsremainunknown. ConsideringtogethertheresilienceoftheCA2regionanditsrolecontrollingnetworkexcitability,Ihypothesize thatinTLEtheCA2regionactsasacriticalhubsupportingthegenerationandpropagationofepileptiform activityinthehippocampalnetwork.Inaninvitromodelofpharmacologically-inducedepileptiformactivity acutesilencingofCA2PNsreducedpopulationburstinginCA1.Preliminarydatafromthepilocarpinemouse modelofTLEsuggestsenhancedexcitatorysynapticinputtoCA2inepilepticmiceandincreasedintrinsic excitabilityofCA2PNs.Furthermore,preliminarydatafromacollaborativestudybetweenourlaboratoryand thatofHelenScharfmanattheNathanKlineInstitutesuggestthatchronicsilencingofCA2inpilocarpine- treatedmicemayreducethefrequencyofspontaneousseizures.ThecontributionoftheCA2subfieldto hippocampalcircuitryandphysiologyremainsincompletelyunderstoodandchangestoCA2circuitryinTLE havenotbeeninvestigated.InadditiontoreceivinginputfromdentategyrusgranulecellsandCA3PNs,CA2 PNsreceiveexceptionallystrongexcitatoryinputfromtheentorhinalcortex.Inturn,CA2axonsprojectforward toCA1,extendbackwardsthroughoutCA3,andformlocalrecurrentconnectionsthatexciteotherCA2PNs. CA2back-projectionsalsoenterthehilusoftheDG,butthiscircuithasnotbeencharacterized.Thus,CA2, CA3,andtheDGtogetherformahighlyinterconnectedrecurrentnetworkthatmaybecomeahyperexcitable hubunderpathologicalconditions.ItisessentialtodefinehowCA2circuitrychangesinchronicepilepsy,and inturn,howthesealteredcircuitscontributetopathophysiologicalactivity.Toaddressthesegapsin knowledge,IwilluseoptogeneticapproachesinvitroandinvivousingtheAmigo2-Cremouseline,which drivesexpressionselectivelyinCA2pyramidalneurons.UsingthepilocarpinemousemodelofTLE,Iwill characterizeCA2circuitryinnormalandepilepticmiceandidentifythechangestoCA2circuitrythat accompanyepileptogenesisanddetermineifmodulationofCA2activityinfluenceschronicseizures.These experimentswilladvanceourunderstandingoftheroleoftheCA2regionincontrollinghippocampalnetwork excitabilityandthegenerationofseizuresinamodelofmesialtemporallobeepilepsy.

Public Health Relevance

Epilepsyisoneofthemostcommonneurologicaldisorders,affectingapproximately1%ofthe population,yetroughlyonethirdofthesepatientsexperiencerefractoryepilepsywithseizuresthatarenot effectivelycontrolledbyavailableantiepilepticdrugs1,2.TheCA2subfieldofthehippocampusexhibitsaunique geneticandmolecularprofileandisresilienttohippocampalsclerosisinmesialtemporallobeepilepsy(MTLE). TheexperimentsoutlinedinthisproposalwillrevealhowCA2circuitrychangesinMTLEandprovideinsight intowhethertherapeuticapproachesthattargetCA2couldbeusedtomitigateorpreventseizures.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS113466-01
Application #
9835439
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Leenders, Miriam
Project Start
2019-09-01
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Neurosciences
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032