Abstract

Agoalofbasicmentalhealthresearchistounderstandthemolecular,cellularandcircuitlevelsubstratesthat contributetoneuropsychiatricdisorders.Thegoalofthisprojectistobetterunderstandtheprinciples underlyingcircuitdysfunctionassociatedwithcognitiveandsocialimpairmentscommontothesedisorders.A promisingapproachtobetterunderstandthesesubstratesistoperformin-depthstudiesinanimalmodelswith highconstructandfacevalidities.DenovopathogenicSYNGAP1mutationsleadingtohaploinsufficiency causeonethemostcommongeneticallydefinedandnon-inheritedformsofintellectualdisability(ID)with autismspectrumdisorder(ASD;?termedMRD5;?OMIN#612621).Studiessupportedbythefirstbudgetperiod identifiedSyngap1heterozygousKOmiceasanoutstandinggeneticmodelofASDwithID.Usingthismodel, wediscoveredadevelopmentalsensitiveperiodofSyngap1functionthatpromotestheproperfunctionof corticalnetworks.Theneurobiologicalstudieswepublishedinthelastperiodweresignificantbecausethey identifiedthedevelopmentaltimingofdendriteandspinematurationselectivitywithinforebrainexcitatory neuronsasacriticalsubstratethatshapesbrainfunctionrelevanttocognitiveandsocialdevelopment. Forthiscompetitiverenewal,wewillbuildonourdiscoveriesinthefirstbudgetperiodbystudyingthekey substratesofcircuitdysfunctionintheSyngap1modelbyprobinghowthisgeneregulatescorticalsensory processingrelevanttocognitionandlearning.Thisapproachissignificantbecausesensoryimpairmentsare extremelycommoninASD/IDandtheseimpairmentsinfluencebehavioraladaptations,includinglearning. Syngap1patientsexpresssensoryabnormalitiesrelatedtotouchandpain.However,thecircuitabnormalities thatunderliesensorydysfunctionareunclear.Thus,ourapproachisinnovativebecausestudieswillbe performedinthemousesomatosensorycortex,whichwillenablepowerfulinvivoexperimentsthatarecapable ofdirectlylinkingcellular-andcircuit-levelfunctionalimpairmentstosensory-basedlearningandbehavioral abnormalities.
The firstAim willinvestigatethecellularmechanismsunderlyingimpairedsomatosensorycortex networkfunctioncausedbypathogenicSyngap1mutations,withanemphasisonhownetwork-levelE/I imbalancesemergewithincorticalcircuitsthatdirectlyencodesensoryrepresentations.Researchproposedin thesecondAimwilldeterminethecellularmechanismsthatcontributetosensory-drivenlearningimpairments inSyngap1mice.Theimpactofthesestudiesisthattheyareexpectedtoadvanceourunderstandinghow corticalcircuitdysfunctionleadstobehavioralimpairmentsassociatedwithASD/ID.

Public Health Relevance

ASD and ID reflect dysfunction of developing neural circuits that drive impaired behavior and cognition. The cellular mechanisms that cause circuit dysfunction remain unclear; thus, this project Aims to discover novel circuit-level substrates that may explain the origins of behavioral and cognitive abnormalities associated with these neuropsychiatric disorders. The knowledge gained from these studies is expected to help direct improved therapeutic approaches to treat impaired cognitive and behavioral impairments common to ASD and ID.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096847-07
Application #
9696406
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Panchision, David M
Project Start
2012-09-01
Project End
2023-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458

  Publications

Michaelson, Sheldon D; Ozkan, Emin D; Aceti, Massimiliano et al. (2018) SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Nat Neurosci 21:1-13
Kilinc, Murat; Creson, Thomas; Rojas, Camilo et al. (2018) Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders. Mol Cell Neurosci 91:140-150
Young, E J; Blouin, A M; Briggs, S B et al. (2016) Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use. Mol Psychiatry 21:615-23
Ogden, Kevin K; Ozkan, Emin D; Rumbaugh, Gavin (2016) Prioritizing the development of mouse models for childhood brain disorders. Neuropharmacology 100:2-16
Aceti, Massimiliano; Creson, Thomas K; Vaissiere, Thomas et al. (2015) Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry 77:805-15
Ozkan, Emin D; Aceti, Massimiliano; Creson, Thomas K et al. (2015) Input-specific regulation of hippocampal circuit maturation by non-muscle myosin IIB. J Neurochem 134:429-44
Zhou, Minghai; Ottenberg, Gregory; Sferrazza, Gian Franco et al. (2015) Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment. Brain 138:992-1008
Rumbaugh, Gavin; Sillivan, Stephanie E; Ozkan, Emin D et al. (2015) Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue. Neuropsychopharmacology 40:2307-16
Aguilar-Valles, Argel; Vaissière, Thomas; Griggs, Erica M et al. (2014) Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation. Biol Psychiatry 76:57-65
Ozkan, Emin D; Creson, Thomas K; Kramár, Enikö A et al. (2014) Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 82:1317-33

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